Hetero biaryl derivatives as matrix metalloproteinase inhibitors

ABSTRACT

This invention provides compounds defined by Formula I 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof,
 
wherein R 1 , Q, S, T, U, V, and R 2  are as defined in the specification. The invention also provides pharmaceutical compositions and methods of treating diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application under 35 U.S.C. §121 and claims benefit of priority from United States nonprovisionalpatent application Ser. No. 10/634,709, filed Aug. 5, 2003, now allowed,and U.S. Provisional Patent Application No. 60/403,162, filed Aug. 13,2002.

FIELD OF THE INVENTION

This invention relates to hetero biaryl derivatives which inhibit matrixmetalloproteinase enzymes and thus are useful for treating diseasesresulting from MMP-mediated tissue breakdown such as heart disease,cardiac insufficiency, inflammatory bowel disease, multiple sclerosis,osteo- and rheumatoid arthritis, arthritis other than osteo- orrheumatoid arthritis, heart failure, age-related macular degeneration,chronic obstructive pulmonary disease, asthma, periodontal diseases,psoriasis, atherosclerosis, and osteoporosis.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (sometimes referred to as MMPs) are naturallyoccurring enzymes found in most mammals. Over-expression and activationof MMPs, or an imbalance between MMPs and inhibitors of MMPs, have beensuggested as factors in the pathogenesis of diseases characterized bythe breakdown of extracellular matrix or connective tissues.

Stromelysin-1 and gelatinase A are members of the MMP family. Othermembers include fibroblast collagenase (MMP-1), neutrophil collagenase(MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2(MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3(MMP-13), TNF-alpha converting enzyme (TACE), and other newly discoveredmembrane-associated matrix metalloproteinases (Sato H., Takino T., OkadaY., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). These enzymes have been implicated with a number of diseaseswhich result from breakdown of connective tissue, including suchdiseases as rheumatoid arthritis, osteoarthritis, osteoporosis,periodontitis, multiple sclerosis, gingivitis, corneal epidermal andgastric ulceration, atherosclerosis, neointimal proliferation whichleads to restenosis and ischemic heart failure, and tumor metastasis. Amethod for preventing and treating these and other diseases is nowrecognized to be by inhibiting matrix metalloproteinase enzymes, therebycurtailing and/or eliminating the breakdown of connective tissues thatresults in the disease states.

There is a catalytic zinc domain in matrix metalloproteinases that istypically the focal point for inhibitor design. The modification ofsubstrates by introducing zinc-chelating groups has generated potentinhibitors such as peptide hydroxamates and thiol-containing peptides.Peptide hydroxamates and the natural endogenous inhibitors of MMPs(TIMPs) have been used successfully to treat animal models of cancer andinflammation. MMP inhibitors have also been used to prevent and treatcongestive heart failure and other cardiovascular diseases, U.S. Pat.No. 5,948,780.

A major limitation on the use of currently known MMP inhibitors is theirlack of specificity for any particular enzyme. Recent data hasestablished that specific MMP enzymes are associated with some diseases,with no effect on others. The MMPs are generally categorized based ontheir substrate specificity, and indeed the collagenase subfamily ofMMP-1, MMP-8, and MMP-13 selectively cleave native interstitialcollagens, and thus are associated only with diseases linked to suchinterstitial collagen tissue. This is evidenced by the recent discoverythat MMP-13 alone is over expressed in breast carcinoma, while MMP-1alone is over expressed in papillary carcinoma (see Chen et al., J. Am.Chem. Soc., 2000; 122:9648-9654).

Selective inhibitors of MMP-13 include a compound named WAY-170523,which has been reported by Chen et al., supra., 2000, and othercompounds are reported in PCT International Patent ApplicationPublication numbers WO 01/63244; WO 00/09485; WO 01/12611; WO 02/34726;and WO 02/34753, and European Patent Application numbers EP 935,963 andEP 1,138,680. Further, U.S. Pat. No. 6,008,243 discloses inhibitors ofMMP-13. However, no selective or nonselective inhibitor of MMP-13 hasbeen approved and marketed for the treatment of any disease in anymammal. Accordingly, the need continues to find new low molecular weightcompounds that are potent and selective MMP inhibitors, and that have anacceptable therapeutic index of toxicity/potency to make them amenablefor use clinically in the prevention and treatment of the associateddisease states. An object of this invention is to provide a group ofselective MMP-13 inhibitor compounds characterized as being heterobiaryl derivatives.

SUMMARY OF THE INVENTION

This invention provides an hetero biaryl derived compound defined byFormula I.

Accordingly, embodiments of the invention include:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ and R² independently are selected from:

H;

C₁-C₆ alkyl;

Substituted C₁-C₆ alkyl;

C₂-C₆ alkenyl;

Substituted C₂-C₆ alkenyl;

C₂-C₆ alkynyl;

Substituted C₂-C₆ alkynyl;

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl;

C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);

Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);

3- to 6-membered heterocycloalkyl;

Substituted 3- to 6-membered heterocycloalkyl;

3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

Substituted 3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

Phenyl-(C₁-C₆ alkylenyl);

Substituted phenyl-(C₁-C₆ alkylenyl);

Naphthyl-(C₁-C₆ alkylenyl);

Substituted naphthyl-(C₁-C₆ alkylenyl);

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl;

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

R³O—(C₁-C₆ alkylenyl);

Substituted R³O—(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5- or 6-membered heteroaryl;

Substituted 5- or 6-membered heteroaryl;

8- to 10-membered heterobiaryl;

Substituted 8- to 10-membered heterobiaryl;

Phenyl-O—(C₁-C₈ alkylenyl);

Substituted phenyl-O—(C₁-C₈ alkylenyl);

Phenyl-S—(C₁-C₈ alkylenyl);

Substituted phenyl-S—(C₁-C₈ alkylenyl);

Phenyl-S(O)—(C₁-C₈ alkylenyl);

Substituted phenyl-S(O)—(C₁-C₈ alkylenyl);

Phenyl-S(O)₂—(C₁-C₈ alkylenyl); and

Substituted phenyl-S(O)₂—(C₁-C₈ alkylenyl);

-   wherein R¹ and R² are not both selected from:

H;

C₁-C₆ alkyl;

C₂-C₆ alkenyl;

C₂-C₆ alkynyl; and

C₃-C₆ cycloalkyl;

-   Each R³ independently is selected from:

H;

C₁-C₆ alkyl;

Substituted C₁-C₆ alkyl;

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl;

Phenyl-(C₁-C₆ alkylenyl);

Substituted phenyl-(C₁-C₆ alkylenyl);

Naphthyl-(C₁-C₆ alkylenyl);

Substituted naphthyl-(C₁-C₆ alkylenyl);

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl;

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

S, T, U, and W each are C—R⁴; orOne of S, T, U, and W is N and the other three of S, T, U, and W areC—R⁴; orTwo of S, T, U, and W are N and the other two of S, T, U, and W areC—R⁴; orT is C—R⁴ and S, U, and W are each N; or

-   U is C—R⁴ and S, T, and W are each N; or-   S is C—R⁴ and T, U, and W are each N;-   Each R⁴ independently is selected from:

H;

F;

CH₃;

CF₃;

C(O)H;

CN;

HO;

CH₃O;

C(F)H₂O;

C(H)F₂O; and

CF₃O;

-   V is a 5-membered heteroarylenyl; and-   Q is selected from:

OCH₂;

N(R⁶)CH₂;

OC(O);

CH(R⁶)C(O);

OC(NR⁶);

CH(R⁶)C(NR⁶);

N(R⁶)C(O);

N(R⁶)C(S);

N(R⁶)C(NR⁶);

N(R⁶)CH₂;

SC(O);

CH(R⁶)C(S);

SC(NR⁶);

-   trans-(H)C═C(H);-   cis-(H)C═C(H);

C≡C;

CH₂C≡C;

C≡CCH₂;

CF₂C≡C;

C≡CCF₂;

-   V is C(O)O, C(S)O, C(O)N(R⁵), or C(S)N(R⁵); and-   Q is selected from:

OCH₂;

N(R⁶)CH₂;

CH(R⁶)C(O);

OC(NR⁶);

CH(R⁶)C(NR⁶);

N(R⁶)C(NR⁶);

N(R⁶)CH₂;

CH(R⁶)C(S);

SC(NR⁶);

trans-(H)C═C(H);

cis-(H)C═C(H);

C≡CCH₂;

C≡CCF₂;

-   R⁵ is H or C₁-C₆ alkyl;-   R⁶ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl; 3- to 6-membered    heterocycloalkyl; phenyl; benzyl; or 5- or 6-membered heteroaryl;-   X is O, S, N(H), or N(C₁-C₆ alkyl);-   Each V¹ is independently C(H) or N;    Each “substituted” group contains from 1 to 4 substituents, each    independently on a carbon or nitrogen atom, independently selected    from:

C₁-C₆ alkyl;

C₂-C₆ alkenyl;

C₂-C₆ alkynyl;

C₃-C₆ cycloalkyl;

C₃-C₆ cycloalkylmethyl;

Phenyl;

Phenylmethyl;

3- to 6-membered heterocycloalkyl;

3- to 6-membered heterocycloalkylmethyl;

cyano;

CF₃;

(C₁-C₆ alkyl)-OC(O);

HOCH₂;

(C₁-C₆ alkyl)-OCH₂;

H₂NCH₂;

(C₁-C₆ alkyl)-N(H)CH₂;

(C₁-C₆ alkyl)₂-NCH₂;

N(H)₂C(O);

(C₁-C₆ alkyl)-N(H)C(O);

(C₁-C₆ alkyl)₂-NC(O);

N(H)₂C(O)N(H);

(C₁-C₆ alkyl)-N(H)C(O)N(H); vN(H)₂C(O)N(C₁-C₆ alkyl);

(C₁-C₆ alkyl)-N(H)C(O)N(C₁-C₆ alkyl);

(C₁-C₆ alkyl)₂-NC(O)N(H);

(C₁-C₆ alkyl)₂-NC(O)N(C₁-C₆ alkyl);

N(H)₂C(O)O;

(C₁-C₆ alkyl)-N(H)C(O)O;

(C₁-C₆ alkyl)₂-NC(O)O;

HO;

(C₁-C₆ alkyl)-O;

CF₃O;

CF₂(H)O;

CF(H)₂O;

H₂N;

(C₁-C₆ alkyl)-N(H);

(C₁-C₆ alkyl)₂-N;

O₂N;

(C₁-C₆ alkyl)-S;

(C₁-C₆ alkyl)-S(O);

(C₁-C₆ alkyl)-S(O)₂;

(C₁-C₆ alkyl)₂-NS(O)₂;

(C₁-C₆ alkyl)-S(O)₂—N(H)—C(O)—(C₁-C₈ alkylenyl)_(m); and

(C₁-C₆ alkyl)-C(O)—N(H)—S(O)₂—(C₁-C₈ alkylenyl)_(m);

wherein each substituent on a carbon atom may further be independentlyselected from:

Halo;

HO₂C; and

OCH₂O, wherein each 0 is bonded to adjacent carbon atoms to form a5-membered ring;

wherein 2 substituents may be taken together with a carbon atom to whichthey are both bonded to form the group C═O;wherein two adjacent, substantially sp² carbon atoms may be takentogether with a diradical substituent to form a cyclic diradicalselected from:

-   R is H or C₁-C₆ alkyl;-   m is an integer of 0 or 1;-   wherein each 5-membered heteroarylenyl independently is a 5-membered    ring containing carbon atoms and from 1 to 4 heteroatoms selected    from 1 O , 1 S, 1 NH, 1 N(C₁-C₆ alkyl), and 4 N, wherein the O and S    atoms are not both present, and wherein the heteroarylenyl may    optionally be unsubstituted or substituted with 1 substituent    selected from fluoro, methyl, hydroxy, trifluoromethyl, cyano, and    acetyl;-   wherein each heterocycloalkyl is a ring that contains carbon atoms    and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O),    1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆ alkyl), and wherein when two O    atoms or one O atom and one S atom are present, the two O atoms or    one O atom and one S atom are not bonded to each other, and wherein    the ring is saturated or optionally contains one carbon-carbon or    carbon-nitrogen double bond;-   wherein each 5-membered heteroaryl contains carbon atoms and from 1    to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1    N(C₁-C₆ alkyl), and 4 N, and each 6-membered heteroaryl contains    carbon atoms and 1 or 2 heteroatoms independently selected from    N,N(H), and N(C₁-C₆ alkyl), and 5- and 6-membered heteroaryl are    monocyclic rings; and 9- and 10-membered heteroaryl are 6,5-fused    and 6,6-fused bicyclic rings, respectively, wherein at least 1 of    the 2 fused rings of a bicyclic ring is aromatic, and wherein when    the O and S atoms both are present, the O and S atoms are not bonded    to each other;-   wherein with any (C₁-C₆ alkyl)₂-N group, the C₁-C₆ alkyl groups may    be optionally taken together with the nitrogen atom to which they    are attached to form a 5- or 6-membered heterocycloalkyl; and-   wherein each group and each substituent recited above is    independently selected.    2. The compound according to Embodiment 1, or a pharmaceutically    acceptable salt thereof, wherein V is selected from the groups:

wherein X is O, S, N(H), or N(C₁-C₆ alkyl) and V may optionally beunsubstituted or substituted at C(H) or N(H) with 1 substituent selectedfrom fluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetyl.

3. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is selected from the groups:

wherein X is O, S, N(H), or N(C₁-C₆ alkyl), R⁴ is H or C₁-C₆ alkyl, andV may optionally be unsubstituted or substituted at C(H) or N(H) with 1substituent selected from fluoro, methyl, hydroxy, trifluoromethyl,cyano, and acetyl.4. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is selected from the groups:

wherein X is O, S, N(H), or N(C₁-C₆ alkyl), Y is O, S, or N, and R⁴ is Hor C₁-C₆ alkyl, and V may optionally be unsubstituted or substituted atC(H) or N(H) with 1 substituent selected from fluoro, methyl, hydroxy,trifluoromethyl, cyano, and acetyl.5. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is selected from the groups:

wherein X is O, S, N(H), or N(C₁-C₆ alkyl), and V may optionally beunsubstituted or substituted at C(H) with 1 substituent selected fromfluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetyl.6. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is selected from the groups:

wherein X is O, S, N(H), or N(C₁-C₆ alkyl), and V may optionally beunsubstituted or substituted at C(H) with 1 substituent selected fromfluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetyl.7. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is selected from the groups:

8. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is C(O)N(R⁵).9. The compound according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein V is C(O)O.10. The compound according to any one of Embodiments 1 to 7, or apharmaceutically acceptable salt thereof, wherein Q is C≡C, CH₂C≡C, orCF₂C≡C11. The compound according to any one of Embodiments 1 to 7, or apharmaceutically acceptable salt thereof, wherein Q is OC(O).12. The compound according to any one of Embodiments 1 to 7, or apharmaceutically acceptable salt thereof, wherein Q is N(R⁶)C(O).13. The compound according to any one of Embodiments 1 to 7, or apharmaceutically acceptable salt thereof, wherein Q is N(H)C(O).14. The compound according to any one of Embodiments 1 to 9, or apharmaceutically acceptable salt thereof, wherein Q is N(H)CH₂ orN(CH₃)CH₂.15. The compound according to any one of Embodiments 1 to 9, or apharmaceutically acceptable salt thereof, wherein Q is C≡CCH₂ or C≡CCF₂.16. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is independently selected from:

Phenyl-(C₁-C₆ alkylenyl); and

Substituted phenyl-(C₁-C₆ alkylenyl);

wherein each group and each substituent is independently selected.17. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein each of R¹ and R² areindependently selected from:

Phenyl-(C₁-C₆ alkylenyl); and

Substituted phenyl-(C₁-C₆ alkylenyl);

wherein each group and each substituent is independently selected.18. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is independently selected from:

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused    bicyclic rings, respectively, wherein at least 1 of the 2 fused    rings of a bicyclic ring is aromatic, and wherein when the O and S    atoms both are present, the O and S atoms are not bonded to each    other; and    wherein each group and each substituent is independently selected.    19. The compound according to any one of Embodiments 1 to 15, or a    pharmaceutically acceptable salt thereof, wherein each of R¹ and R²    is independently selected from:

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused    bicyclic rings, respectively, wherein at least 1 of the 2 fused    rings of a bicyclic ring is aromatic, and wherein when the O and S    atoms both are present, the O and S atoms are not bonded to each    other; and    wherein each group and each substituent is independently selected.    20. The compound according to any one of Embodiments 1 to 15, 18,    and 19, or a pharmaceutically acceptable salt thereof, wherein at    least one of R¹ and R² is independently selected from:

5-, 6-, and 9-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9-membered heteroaryl is 6,5-fused bicyclic ring, wherein    at least 1 of the 2 fused rings of a bicyclic ring is aromatic, and    wherein when the O and S atoms both are present, the O and S atoms    are not bonded to each other; and-   wherein each group and each substituent is independently selected.    21. The compound according to any one of Embodiments 1 to 15, or a    pharmaceutically acceptable salt thereof, wherein at least one of R¹    and R² is independently selected from:

3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl); and

Substituted 3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

-   wherein each heterocycloalkyl is a ring that contains carbon atoms    and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O),    1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆ alkyl), and wherein when two O    atoms or one O atom and one S atom are present, the two O atoms or    one O atom and one S atom are not bonded to each other, and wherein    the ring is saturated or optionally contains one carbon-carbon or    carbon-nitrogen double bond; and-   wherein each group and each substituent recited above is    independently selected.    22. The compound according to any one of Embodiments 1 to 15, or a    pharmaceutically acceptable salt thereof, wherein one of R¹ and R²    is independently selected from:

C₂-C₆ alkenyl; and

Substituted C₂-C₆ alkenyl.

23. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₁-C₆ alkyl; and

Substituted C₁-C₆ alkyl.

24. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₂-C₆ alkynyl; and

Substituted C₂-C₆ alkynyl.

25. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is independently selected from:

C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl); and

Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl).

26. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl

3- to 6-membered heterocycloalkyl;

Substituted 3- to 6-membered heterocycloalkyl;

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl; and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

27. The compound according to any one of Embodiments 1 to 15, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² is H.28. The compound according to any one of Embodiments 1 to 27, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂, C(CH₃)₂, C(═O), or CF₂.29. The compound according to any one of Embodiments 1 to 28, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂.30. The compound according to any one of Embodiments 1 to 29, or apharmaceutically acceptable salt thereof, wherein at least onesubstituent is selected from the groups:

CO₂H;

CO₂CH₃;

CH₃O;

F;

Cl;

CN;

CF₃;

CH₃S(O)₂;

CH₃; or

wherein at least two substituents are Cl and F, 2 F, or OCH₂O, whereineach O is bonded to adjacent carbon atoms to form a 5-membered ring.31. The compound according to any one of Embodiments 1 to 30, or apharmaceutically acceptable salt thereof, wherein S, T, U, and W areeach CH.32. The compound according to any one of Embodiments 1 to 30, or apharmaceutically acceptable salt thereof, wherein S is C—OCH₃ and T, U,and W are each CH.33. A compound of Formula II

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ and R² independently are selected from:

H;

C₁-C₆ alkyl;

Substituted C₁-C₆ alkyl;

C₂-C₆ alkenyl;

Substituted C₂-C₆ alkenyl;

C₂-C₆ alkynyl;

Substituted C₂-C₆ alkynyl;

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl;

C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);

Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);

3- to 6-membered heterocycloalkyl;

Substituted 3- to 6-membered heterocycloalkyl;

3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

Substituted 3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

Phenyl-(C₁-C₆ alkylenyl);

Substituted phenyl-(C₁-C₆ alkylenyl);

-   Naphthyl-(C₁-C₆ alkylenyl);

Substituted naphthyl-(C₁-C₆ alkylenyl);

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl;

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

R³O—(C₁-C₆ alkylenyl); and

Substituted R³O—(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5- or 6-membered heteroaryl;

Substituted 5- or 6-membered heteroaryl;

8- to 10-membered heterobiaryl;

Substituted 8- to 10-membered heterobiaryl;

Phenyl-O—(C₁-C₈ alkylenyl);

Substituted phenyl-O—(C₁-C₈ alkylenyl);

Phenyl-S—(C₁-C₈ alkylenyl);

Substituted phenyl-S—(C₁-C₈ alkylenyl);

-   Phenyl-S(O)—(C₁-C₈ alkylenyl);

Substituted phenyl-S(O)—(C₁-C₈ alkylenyl);

Phenyl-S(O)₂—(C₁-C₈ alkylenyl); and

Substituted phenyl-S(O)₂—(C₁-C₈ alkylenyl);

-   wherein R¹ and R² are not both selected from:

H;

C₁-C₆ alkyl;

C₂-C₆ alkenyl;

C₂-C₆ alkynyl; and

C₃-C₆ cycloalkyl;

-   Each R³ independently is selected from:

H;

C₁-C₆ alkyl;

Substituted C₁-C₆ alkyl;

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl;

Phenyl-(C₁-C₆ alkylenyl);

Substituted phenyl-(C₁-C₆ alkylenyl);

Naphthyl-(C₁-C₆ alkylenyl);

Substituted naphthyl-(C₁-C₆ alkylenyl);

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl;

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

-   S, T, and U each are C—R⁴; or-   One of S, T, and U is N and the other two of S, T, and U are C—R⁴;    or-   Two of S, T, and U are N and the other one of S, T, and U is C—R⁴;-   Each R⁴ independently is selected from:

H;

F;

CH₃;

CF₃;

C(O)H;

CN;

HO;

CH₃O;

C(F)H₂O;

C(H)F₂O; and

CF₃O;

-   Q is selected from:

OCH₂;

N(R⁶)CH₂;

OC(O);

CH(R⁶)C(O);

OC(NR⁶);

CH(R⁶)C(NR⁶);

N(R⁶)C(O);

N(R⁶)C(NR⁶);

N(R⁶)CH₂;

SC(O);

CH(R⁶)C(S);

SC(NR⁶);

trans-(H)C═C(H);

cis-(H)C═C(H);

C≡C;

CH₂C≡C;

C≡CCH₂;

CF₂C≡C;

C≡CCF₂;

-   R⁶ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl; 3- to 6-membered    heterocycloalkyl; phenyl; benzyl; or 5- or 6-membered heteroaryl;-   X is O, S, N(H), or N(C₁-C₆ alkyl);-   Each V¹ is independently C(H) or N;-   Each “substituted” group contains from 1 to 4 substituents, each    independently on a carbon or nitrogen atom, independently selected    from:

C₁-C₆ alkyl;

C₂-C₆ alkenyl;

C₂-C₆ alkynyl;

C₃-C₆ cycloalkyl;

C₃-C₆ cycloalkylmethyl;

Phenyl;

Phenylmethyl;

3- to 6-membered heterocycloalkyl;

3- to 6-membered heterocycloalkylmethyl;

cyano;

CF₃;

(C₁-C₆ alkyl)-OC(O);

HOCH₂;

(C₁-C₆ alkyl)-OCH₂;

H₂NCH₂;

(C₁-C₆ alkyl)-N(H)CH₂;

(C₁-C₆ alkyl)₂-NCH₂;

N(H)₂C(O);

(C₁-C₆ alkyl)-N(H)C(O);

(C₁-C₆ alkyl)₂-NC(O);

N(H)₂C(O)N(H);

(C₁-C₆ alkyl)-N(H)C(O)N(H);

N(H)₂C(O)N(C₁-C₆ alkyl);

(C₁-C₆ alkyl)-N(H)C(O)N(C₁-C₆ alkyl);

(C₁-C₆ alkyl)₂-NC(O)N(H);

(C₁-C₆ alkyl)₂-NC(O)N(C₁-C₆ alkyl);

N(H)₂C(O)O;

(C₁-C₆ alkyl)-N(H)C(O)O;

(C₁-C₆ alkyl)₂-NC(O)O;

HO;

(C₁-C₆ alkyl)-O;

CF₃O;

CF₂(H)O;

CF(H)₂O;

H₂N;

(C₁-C₆ alkyl)-N(H);

(C₁-C₆ alkyl)₂-N;

O₂N;

(C₁-C₆ alkyl)-S;

(C₁-C₆ alkyl)-S(O);

(C₁-C₆ alkyl)-S(O)₂;

(C₁-C₆ alkyl)₂-NS(O)₂;

(C₁-C₆ alkyl)-S(O)₂—N(H)—C(O)—(C₁-C₈ alkylenyl)_(m); and (C₁-C₆alkyl)-C(O)—N(H)—S(O)₂—(C₁-C₈ alkylenyl)_(m);

wherein each substituent on a carbon atom may further be independentlyselected from:

Halo;

HO₂C; and

OCH₂O, wherein each 0 is bonded to adjacent carbon atoms to form a5-membered ring;

-   wherein 2 substituents may be taken together with a carbon atom to    which they are both bonded to form the group C═O;    wherein two adjacent, substantially sp² carbon atoms may be taken    together with a diradical substituent to form a cyclic diradical    selected from:

-   R is H or C₁-C₆ alkyl;-   wherein each 5-membered heteroarylenyl independently is a 5-membered    ring containing carbon atoms and from 1 to 4 heteroatoms selected    from 1 O, 1 S, 1 NH, 1 N(C₁-C₆ alkyl), and 4 N, wherein the O and S    atoms are not both present, and wherein the heteroarylenyl may    optionally be unsubstituted or substituted with 1 substituent    selected from fluoro, methyl, hydroxy, trifluoromethyl, cyano, and    acetyl;-   wherein each heterocycloalkyl is a ring that contains carbon atoms    and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O),    1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆ alkyl), and wherein when two O    atoms or one O atom and one S atom are present, the two O atoms or    one O atom and one S atom are not bonded to each other, and wherein    the ring is saturated or optionally contains one carbon-carbon or    carbon-nitrogen double bond;-   wherein each 5-membered heteroaryl contains carbon atoms and from 1    to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1    N(C₁-C₆ alkyl), and 4 N, and each 6-membered heteroaryl contains    carbon atoms and 1 or 2 heteroatoms independently selected from    N,N(H), and N(C₁-C₆ alkyl), and 5- and 6-membered heteroaryl are    monocyclic rings; and 9- and 10-membered heteroaryl are 6,5-fused    and 6,6-fused bicyclic rings, respectively, wherein at least 1 of    the 2 fused rings of a bicyclic ring is aromatic, and wherein when    the O and S atoms both are present, the O and S atoms are not bonded    to each other;-   wherein with any (C₁-C₆ alkyl)₂-N group, the C₁-C₆ alkyl groups may    be optionally taken together with the nitrogen atom to which they    are attached to form a 5- or 6-membered heterocycloalkyl; and-   wherein each group and each substituent recited above is    independently selected.    34. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is OC(O).    35. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is OCH₂.    36. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is N(R⁶)C(O).    37. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is N(H)C(O).    38. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is N(R⁶)CH₂.    39. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is N(H)CH₂.    40. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is N(CH₃)CH₂.    41. The compound according to Embodiment 33, or a pharmaceutically    acceptable salt thereof, wherein Q is C≡C, CH₂C≡C, C≡CCH₂, CF₂C≡C,    or C≡CCF₂.    42. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein at least one of R¹    and R² is independently selected from:

Phenyl-(C₁-C₆ alkylenyl); and

Substituted phenyl-(C₁-C₆ alkylenyl);

-   wherein each group and each substituent is independently selected.    43. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein each of R¹ and R²    are independently selected from:

Phenyl-(C₁-C₆ alkylenyl); and

Substituted phenyl-(C₁-C₆ alkylenyl);

-   wherein each group and each substituent is independently selected.    44. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein at least one of R¹    and R² is independently selected from:

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused    bicyclic rings, respectively, wherein at least 1 of the 2 fused    rings of a bicyclic ring is aromatic, and wherein when the O and S    atoms both are present, the O and S atoms are not bonded to each    other; and-   wherein each group and each substituent is independently selected.    45. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein each of R¹ and R²    is independently selected from:

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused    bicyclic rings, respectively, wherein at least 1 of the 2 fused    rings of a bicyclic ring is aromatic, and wherein when the O and S    atoms both are present, the O and S atoms are not bonded to each    other; and-   wherein each group and each substituent is independently selected.    46. The compound according to any one of Embodiments 33 to 41, 44,    and 45, or a pharmaceutically acceptable salt thereof, wherein at    least one of R¹ and R² is independently selected from:

5-, 6-, and 9-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9-membered heteroaryl is 6,5-fused bicyclic ring, wherein    at least 1 of the 2 fused rings of a bicyclic ring is aromatic, and    wherein when the O and S atoms both are present, the O and S atoms    are not bonded to each other; and-   wherein each group and each substituent is independently selected.    47. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein at least one of R¹    and R² is independently selected from:

3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl); and

Substituted 3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl);

-   wherein each heterocycloalkyl is a ring that contains carbon atoms    and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O),    1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆ alkyl), and wherein when two O    atoms or one O atom and one S atom are present, the two O atoms or    one O atom and one S atom are not bonded to each other, and wherein    the ring is saturated or optionally contains one carbon-carbon or    carbon-nitrogen double bond; and-   wherein each group and each substituent recited above is    independently selected.    48. The compound according to any one of Embodiments 33 to 41, or a    pharmaceutically acceptable salt thereof, wherein one of R¹ and R²    is independently selected from:

C₂-C₆ alkenyl; and

Substituted C₂-C₆ alkenyl.

49. The compound according to any one of Embodiments 33 to 41, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₁-C₆ alkyl; and

Substituted C₁-C₆ alkyl.

50. The compound according to any one of Embodiments 33 to 41, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₂-C₆ alkynyl; and

Substituted C₂-C₆ alkynyl.

51. The compound according to any one of Embodiments 33 to 41, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is independently selected from:

C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl); and

Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl).

52. The compound according to any one of Embodiments 33 to 41, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² isindependently selected from:

C₃-C₆ cycloalkyl;

Substituted C₃-C₆ cycloalkyl

3- to 6-membered heterocycloalkyl;

Substituted 3- to 6-membered heterocycloalkyl;

Phenyl;

Substituted phenyl;

Naphthyl;

Substituted naphthyl;

5-, 6-, 9-, and 10-membered heteroaryl; and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl;

53. The compound according to any one of Embodiments 33 to 41, or apharmaceutically acceptable salt thereof, wherein one of R¹ and R² is H.54. The compound according to any one of Embodiments 33 to 53, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂, C(CH₃)₂, C(═O), or CF₂.55. The compound according to any one of Embodiments 33 to 54, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂.56. The compound according to any one of Embodiments 33 to 55, or apharmaceutically acceptable salt thereof, wherein at least onesubstituent is selected from the groups:

CO₂H;

CO₂CH₃;

CH₃O;

F;

Cl;

CN;

CF₃;

CH₃S(O)₂;

CH₃; or

wherein at least two substituents are Cl and F, 2 F, or OCH₂O, whereineach 0 is bonded to adjacent carbon atoms to form a 5-membered ring.57. The compound according to any one of Embodiments 33 to 56, or apharmaceutically acceptable salt thereof, wherein S, T, and U are eachCH.58. The compound according to any one of Embodiments 33 to 57, or apharmaceutically acceptable salt thereof, wherein S is C—OCH₃ and T andU are each CH.59. The compound according to Embodiment 33, selected from:

-   4-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid methyl ester;-   4-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid;-   4-({3-[2-(3-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid methyl ester;-   4-({3-[2-(3-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid;-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(4-morpholin-4-ylmethyl-benzyl)-benzamide;-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(3-trifluoromethyl-benzyl)-benzamide;-   N-Benzyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-trifluoromethyl-benzyl)-benzamide;    and-   N-(4-Methoxy-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;    or

a pharmaceutically acceptable salt thereof.

60. The compound according to Embodiment 33, selected from:

-   4-({3-[2-(4-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid methyl ester;-   4-({3-[2-(4-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid;-   4-({3-[2-(3-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid methyl ester;-   4-({3-[2-(3-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid;-   N-(3-Chloro-4-fluoro-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;-   N-(2,3-Difluoro-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;    and-   N-(4-Fluoro-benzyl)-2-methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;    or

a pharmaceutically acceptable salt thereof.

61. The compound according to Embodiment 33, named:

-   N-Benzyl-3-[2-(4-cyano-benzyl)-2H-tetrazol-5-yl]-benzamide; or

a pharmaceutically acceptable salt thereof.

62. The compound according to Embodiment 33, named:

-   4-{[3-(2-Thiazol-2-ylmethyl-2H-tetrazol-5-yl)-benzoylamino]-methyl}-benzoic    acid methyl ester; or

a pharmaceutically acceptable salt thereof.

63. The compound according to Embodiment 33, selected from:

-   4-{[3-(2-But-2-enyl-2H-tetrazol-5-yl)-benzoylamino]-methyl}benzoic    acid methyl ester;-   N-Benzyl-3-(2-but-2-enyl-2H-tetrazol-5-yl)-benzamide; and-   3-(2-But-2-enyl-2H-tetrazol-5-yl)-N-(3-methoxy-benzyl)-benzamide; or

a pharmaceutically acceptable salt thereof.

64. The compound according to Embodiment 33, selected from:

-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-thiazol-2-ylmethyl-benzamide;-   N-2,1,3-Benzothiadiazol-5-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-methoxy-pyridin-4-ylmethyl)-benzamide;-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-pyridin-4-ylmethyl-benzamide;-   N-1,3-Benzodioxol-5-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;    and-   N-Furan-2-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide;    or

a pharmaceutically acceptable salt thereof.

65. The compound according to Embodiment 33, selected from:

-   4-(5-{3-[(Pyridin-4-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid;-   4-(5-{3-[(Pyridin-3-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; and-   4-(5-{3-[(2-Methoxy-pyridin-4-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

66. The compound according to Embodiment 33, named:

-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-pyridin-4-yl-ethyl)-benzamide;    or

a pharmaceutically acceptable salt thereof.

67. The compound according to Embodiment 33, named:

-   N-Isopropyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide; or

a pharmaceutically acceptable salt thereof.

68. The compound according to Embodiment 33, named:

-   3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(1-phenyl-ethyl)-benzamide;    or

a pharmaceutically acceptable salt thereof.

69. The compound according to Embodiment 33, named:

-   4-(5-{3-[(Methyl-pyridin-3-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

70. The compound according to Embodiment 33, selected from:

-   4-({2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid;-   4-({2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic    acid; and-   2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-N-(4-trifluoromethyl-benzyl)-benzamide;    or

a pharmaceutically acceptable salt thereof.

71. The compound according to Embodiment 33, named:

-   Benzyl {3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzyl}-amine    hydrochloride; or

a pharmaceutically acceptable salt thereof.

72. The compound according to Embodiment 33, selected from:

-   (4-Methanesulfonyl-benzyl)-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzyl}-amine;    and-   4-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5yl]-benzylamino}-methyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

73. The compound according to Embodiment 33, selected from:

-   4-{3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzyloxymethyl}-benzoic    acid; and-   4-{3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzyloxy}-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

74. The compound according to Embodiment 33, selected from:

-   4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid; and-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

75. The compound according to Embodiment 33, named:

-   4-{5-[3-(3-Methyl-3-phenyl-but-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

76. The compound according to Embodiment 33, named:

-   4-{5-[3-(3-Imidazol-1-yl-prop-1-ynyl)-phenyl]-terazol-2-ylmethyl}-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

Another aspect of this invention is a compound of Formula I selectedfrom:

-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid;-   [4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenyl]-acetic    acid;-   1-[4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenyl]-cyclopropanecarboxylic    acid;-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzamide;-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-2-methyl-benzoic    acid; and-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-cyclohexanecarboxylic    acid; or

a pharmaceutically acceptable salt thereof.

Another aspect of this invention is a compound of Formula I selectedfrom:

-   2-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-oxazole-4-carboxylic    acid; and-   2-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-thiazole-4-carboxylic    acid; or

a pharmaceutically acceptable salt thereof.

Another aspect of this invention is a compound of Formula I selectedfrom:

-   4-{5-[2-(4-Fluoro-benzylcarbamoyl)-6-methyl-pyridin-4-yl]-tetrazol-2-ylmethyl}-benzoic    acid;-   4-{5-[2-(3,4-Difluoro-benzylcarbamoyl)-pyridin-4-yl]-tetrazol-2-ylmethyl}-benzoic    acid;-   4-{5-[2-(3,4-Difluoro-benzylcarbamoyl)-6-methyl-pyridin-4-yl]-tetrazol-2-ylmethyl}-benzoic    acid; and-   4-(5-{2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyridin-4-yl}-tetrazol-2-ylmethyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

Another aspect of this invention is a compound of Formula I selectedfrom:

-   4-(5-{3-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-yl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoic    acid;-   4-(2-{3-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-oxazol-5-yl)-benzoic    acid;-   4-(2-{3-[5-(4-Chloro-phenyl)-oxazol-2-yl]-phenyl}-oxazol-5-yl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-yl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-yl)-benzoic    acid;-   4-(5-{3-[5-(4-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-yl)-benzoic    acid;-   4-(2-{3-[5-(4-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-oxazol-5-yl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

77. A pharmaceutical composition, comprising a compound of Formula Iaccording to Embodiment 1, or a pharmaceutically acceptable saltthereof, admixed with a pharmaceutically acceptable carrier, excipient,or diluent.78. The pharmaceutical composition according to Embodiment 77,comprising a compound of Formula I according to any one of Embodiments 2to 76, or a pharmaceutically acceptable salt thereof, admixed with apharmaceutically acceptable carrier, excipient, or diluent.79. A method for inhibiting an MMP-13 enzyme in an animal, comprisingadministering to the animal an MMP-13 inhibiting amount of a compound ofFormula I according to Embodiment 1, or a pharmaceutically acceptablesalt thereof.80. The method according to Embodiment 79, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.81. A method for treating a disease mediated by an MMP-13 enzyme,comprising administering to a patient suffering from such a disease anontoxic effective amount of a compound of Formula I according toEmbodiment 1, or a pharmaceutically acceptable salt thereof.82. The method according to Embodiment 81, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.83. A method for treating arthritis, comprising administering to apatient suffering from an arthritis disease a nontoxic antiarthriticeffective amount of a compound of Formula I according to Embodiment 1,or a pharmaceutically acceptable salt thereof.84. The method according to Embodiment 83, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.85. A method for treating osteoarthritis, comprising administering to apatient suffering from osteoarthritis a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.86. The method according to Embodiment 85, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.87. A method for treating rheumatoid arthritis, comprising administeringto a patient suffering from rheumatoid arthritis a nontoxic effectiveamount of a compound of Formula I according to Embodiment 1, or apharmaceutically acceptable salt thereof.88. The method according to Embodiment 87, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.89. A method for treating psoriatic arthritis, comprising administeringto a patient suffering from psoriatic arthritis a nontoxic effectiveamount of a compound of Formula I according to Embodiment 1, or apharmaceutically acceptable salt thereof.90. The method according to Embodiment 89, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.91. A method for treating a cancer, comprising administering to apatient suffering from a cancer a nontoxic anti-cancer effective amountof a compound of Formula I according to Embodiment 1, or apharmaceutically acceptable salt thereof.92. The method according to Embodiment 91, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.93. A method for treating breast carcinoma, comprising administering toa patient suffering from breast carcinoma a nontoxic effective amount ofa compound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.94. The method according to Embodiment 93, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.95. A method for treating atherosclerosis, comprising administering to apatient suffering from atherosclerosis a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.96. The method according to Embodiment 95, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.97. A method for treating inflammation, comprising administering to apatient suffering from inflammation a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.98. The method according to Embodiment 97, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.99. A method for treating heart failure, comprising administering to apatient suffering from heart failure a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.100. The method according to Embodiment 99, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.101. A method for treating age-related macular degeneration, comprisingadministering to a patient suffering from age-related maculardegeneration a nontoxic effective amount of a compound of Formula Iaccording to Embodiment 1, or a pharmaceutically acceptable saltthereof.102. The method according to Embodiment 101, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.103. A method for treating chronic obstructive pulmonary disease,comprising administering to a patient suffering from chronic obstructivepulmonary disease a nontoxic effective amount of a compound of Formula Iaccording to Embodiment 1, or a pharmaceutically acceptable saltthereof.104. The method according to Embodiment 103, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.105. A method for treating heart disease, comprising administering to apatient suffering from heart disease a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.106. The method according to Embodiment 105, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.107. A method for treating multiple sclerosis, comprising administeringto a patient suffering from multiple sclerosis a nontoxic effectiveamount of a compound of Formula I according to Embodiment 1, or apharmaceutically acceptable salt thereof.108. The method according to Embodiment 107, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.109. A method for treating psoriasis, comprising administering to apatient suffering from psoriasis a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.110. The method according to Embodiment 109, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.111. A method for treating asthma, comprising administering to a patientsuffering from asthma a nontoxic effective amount of a compound ofFormula I according to Embodiment 1, or a pharmaceutically acceptablesalt thereof.112. The method according to Embodiment 111, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.113. A method for treating cardiac insufficiency, comprisingadministering to a patient suffering from cardiac insufficiency anontoxic effective amount of a compound of Formula I according toEmbodiment 1, or a pharmaceutically acceptable salt thereof.114. The method according to Embodiment 113, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.115. A method for treating inflammatory bowel disease, comprisingadministering to a patient suffering from inflammatory bowel disease anontoxic effective amount of a compound of Formula I according toEmbodiment 1, or a pharmaceutically acceptable salt thereof.116. The method according to Embodiment 115, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.117. A method for treating osteoporosis, comprising administering to apatient suffering from osteoporosis a nontoxic effective amount of acompound of Formula I according to Embodiment 1, or a pharmaceuticallyacceptable salt thereof.118. The method according to Embodiment 117, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.119. A method for treating periodontal diseases, comprisingadministering to a patient suffering from periodontal diseases anontoxic effective amount of a compound of Formula I according toEmbodiment 1, or a pharmaceutically acceptable salt thereof.120. The method according to Embodiment 119, wherein the compound ofFormula I is according to any one of Embodiments 2 to 76, or apharmaceutically acceptable salt thereof.121. The method according to any one of Embodiments 79 to 120, whereinthe compound of Formula I according to Embodiment 1, or apharmaceutically acceptable salt thereof, is administered as apharmaceutical composition according to Embodiment 77 or 78.122. The compound according to Embodiment 1, wherein S is N and Q isN(H)C(O).123. The compound according to Embodiment 1, wherein W is N and Q isN(H)C(O).

Another aspect of this invention is a method of synthesizing a compoundof Formula I according to the methods described below.

Another aspect of this invention is a compound of Formula Ia

or a pharmaceutically acceptable salt thereof,wherein:

-   R¹ and R² independently are selected from: Substituted C₁-C₆ alkyl,    Substituted C₂-C₆ alkenyl, Substituted C₂-C₆ alkynyl, Substituted    C₃-C₆ cycloalkyl, Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl),    Substituted 3- to 6-membered heterocycloalkyl, Substituted 3- to    6-membered heterocycloalkyl-(C₁-C₆ alkylenyl), Phenyl-(C₁-C₆    alkylenyl), Substituted phenyl-(C₁-C₆ alkylenyl), 5-, 6-, 9-, and    10-membered heteroaryl-(C₁-C₆ alkylenyl), Substituted 5-, 6-, 9-,    and 10-membered heteroaryl-(C₁-C₆ alkylenyl), Phenyl, Substituted    phenyl, 5-, 6-, 9-, and 10-membered heteroaryl, Substituted 5-, 6-,    9-, and 10-membered heteroaryl, R³O—(C₁-C₆ alkylenyl), Substituted    R³O—(C₁-C₆ alkylenyl), Phenyl, Substituted phenyl, 5- or 6-membered    heteroaryl, Substituted 5- or 6-membered heteroaryl, 8- to    10-membered heterobiaryl, Substituted 8- to 10-membered    heterobiaryl, Phenyl-O—(C₁-C₈ alkylenyl), Substituted    phenyl-O—(C₁-C₈ alkylenyl), Phenyl-S—(C₁-C₈ alkylenyl), Substituted    phenyl-S—(C₁-C₈ alkylenyl), Phenyl-S(O)—(C₁-C₈ alkylenyl),    Substituted phenyl-S(O)—(C₁-C₈ alkylenyl), Phenyl-S(O)₂—(C₁-C₈    alkylenyl), and Substituted phenyl-S(O)₂—(C₁-C₈ alkylenyl);-   Each R³ independently is selected from: Substituted C₁-C₆ alkyl,    Substituted C₃-C₆ cycloalkyl, Phenyl-(C₁-C₆ alkylenyl), Substituted    phenyl-(C₁-C₆ alkylenyl), 5-, 6-, 9-, and 10-membered    heteroaryl-(C₁-C₆ alkylenyl), Substituted 5-, 6-, 9-, and    10-membered heteroaryl-(C₁-C₆ alkylenyl), Phenyl, Substituted    phenyl, 5-, 6-, 9-, and 10-membered heteroaryl, Substituted 5-, 6-,    9-, and 10-membered heteroaryl;-   S, T, U, and W each are C—R⁴; or-   One of S, T, U, and W is N and the other three of S, T, U, and W are    C—R⁴; or-   Two of S, T, U, and W are N and the other two of S, T, U, and W are    C—R⁴; or-   T is C—R⁴ and S, U, and W are each N; or-   U is C—R⁴ and S, T, and W are each N; or-   S is C—R⁴ and T, U, and W are each N;-   Each R⁴ independently is selected from: H, F, CH₃, CF₃, C(O)H, CN,    HO, CH₃O, C(F)H₂O, C(H)F₂O, and CF₃O;-   V is a 5-membered heteroarylenyl; and-   Q is selected from: OCH₂, N(R⁶)CH₂, OC(O), CH(R⁶)C(O), OC(NR⁶),    CH(R⁶)C(NR⁶), N(R⁶)C(O), N(R⁶)C(S), N(R⁶)C(NR⁶), N(R⁶)CH₂, SC(O),    CH(R⁶)C(S), SC(NR⁶), trans-(H)C═C(H), cis-(H)C═C(H), C≡C, CH₂C≡C,    C≡CCH₂, CF₂C≡C, C≡CCF₂,

-   V is C(O)O, C(S)O, C(O)N(R⁵), or C(S)N(R⁵); and-   Q is selected from: OCH₂, N(R⁶)CH₂, CH(R⁶)C(O), OC(NR⁶),    CH(R⁶)C(NR⁶), N(R⁶)C(NR⁶), N(R⁶)CH₂, CH(R⁶)C(S), SC(NR⁶),    trans-(H)C═C(H), cis-(H)C═C(H), C≡CCH₂, C≡CCF₂,

-   R⁵ is H or C₁-C₆ alkyl;-   R⁶ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl; 3- to 6-membered    heterocycloalkyl; phenyl; benzyl; or 5- or 6-membered heteroaryl;-   X is O, S, N(H), or N(C₁-C₆ alkyl);-   Each V¹ is independently C(H) or N;-   Each “substituted” group contains from 1 to 4 substituents, each    independently on a carbon or nitrogen atom, independently selected    from:    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,        C₃-C₆ cycloalkylmethyl, Phenyl, Phenylmethyl, 3- to 6-membered        heterocycloalkyl, 3- to 6-membered heterocycloalkylmethyl,        cyano, CF₃, (C₁-C₆ alkyl)-OC(O), HOCH₂, (C₁-C₆ alkyl)-OCH₂,        H₂NCH₂, (C₁-C₆ alkyl)-N(H)CH₂, (C₁-C₆ alkyl)₂-NCH₂, N(H)₂C(O),        (C₁-C₆ alkyl)-N(H)C(O), (C₁-C₆ alkyl)₂-NC(O), N(H)₂C(O)N(H),        (C₁-C₆ alkyl)-N(H)C(O)N(H), N(H)₂C(O)N(C₁-C₆ alkyl), (C₁-C₆        alkyl)-N(H)C(O)N(C₁-C₆ alkyl), (C₁-C₆ alkyl)₂-NC(O)N(H), (C₁-C₆        alkyl)₂-NC(O)N(C₁-C₆ alkyl), N(H)₂C(O)O, (C₁-C₆        alkyl)-N(H)C(O)O, (C₁-C₆ alkyl)₂-NC(O)O, HO, (C₁-C₆ alkyl)-O,        CF₃O, CF₂(H)O, CF(H)₂O, H₂N, (C₁-C₆ alkyl)-N(H), (C₁-C₆        alkyl)₂-N, O₂N, (C₁-C₆ alkyl)-S, (C₁-C₆ alkyl)-S(O), (C₁-C₆        alkyl)-S(O)₂, (C₁-C₆ alkyl)₂-NS(O), (C₁-C₆        alkyl)-S(O)₂—N(H)—C(O)—(C₁-C₈ alkylenyl)_(m), (C₁-C₆        alkyl)-C(O)—N(H)—S(O)₂—(C₁-C₈ alkylenyl)_(m), HO—C(═O)—(C₁-C₃        alkylenyl), HO—C(═O)—(C₃-C₆ cycloalkylen-1-yl), Phenyl        substituted with 1 or two substituents selected from F, Cl, OH,        OCH₃, C≡N, COOH, COOCH₃, C(═O)CH₃, and CF₃, 5- or 6-membered        heteroaryl, 5- or 6-membered heteroaryl substituted with 1        substituent selected from F, Cl, OH, OCH₃, C≡N, COOH, COOCH₃,        C(═O)CH₃, and CF₃, SO₃H, PO₃H₂, and R⁷R^(7a)-(J)_(m)-N(H)CH₂,        wherein m is an integer of 0 or 1; J is N—C(═O); and R⁷ and        R^(7a) are independently selected from hydrogen, C₁-C₆ alkyl,        (C₁-C₆ alkyl)-C(═O), C₁-C₆ alkyl substituted with 1 or 2 OH,        C₁-C₃ alkyl-O—(C₁-C₃ alkylenyl), 5- or 6-membered        heteroaryl-C(═O), and (C₁-C₆ alkyl)-S(O)₂; or R⁷ and R^(7a) may        be taken together with the nitrogen atom to which they are both        bonded to form (i) a 3- to 6-membered heterocycloalkyl,        optionally substituted with a CH₃ or oxo (i.e., ═O), containing        the nitrogen atom, 0 or 1 O or S atoms, and carbon atoms or (ii)        a 5- or 6-membered heteroaryl containing the nitrogen atom, 0 or        1 additional N atom, and carbon atoms;        wherein each substituent on a carbon atom may further be        independently selected from:

Halo;

HO₂C; and

OCH₂O, wherein each 0 is bonded to adjacent carbon atoms to form a5-membered ring;

wherein 2 substituents may be taken together with a carbon atom to whichthey are both bonded to form the group C═O;wherein two adjacent, substantially sp² carbon atoms may be takentogether with a diradical substituent to form a cyclic diradicalselected from:

-   R is H or C₁-C₆ alkyl;-   m is an integer of 0 or 1;-   wherein each 5-membered heteroarylenyl independently is a 5-membered    ring containing carbon atoms and from 1 to 4 heteroatoms selected    from 1 O, 1 S, 1 NH, 1 N(C₁-C₆ alkyl), and 4 N, wherein the O and S    atoms are not both present, and wherein the heteroarylenyl may    optionally be unsubstituted or substituted with 1 substituent    selected from fluoro, methyl, hydroxy, trifluoromethyl, cyano, and    acetyl;-   wherein each heterocycloalkyl is a ring that contains carbon atoms    and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O),    1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆ alkyl), and wherein when two O    atoms or one O atom and one S atom are present, the two O atoms or    one O atom and one S atom are not bonded to each other, and wherein    the ring is saturated or optionally contains one carbon-carbon or    carbon-nitrogen double bond;-   wherein each 5-membered heteroaryl contains carbon atoms and from 1    to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1    N(C₁-C₆ alkyl), and 4 N, and each 6-membered heteroaryl contains    carbon atoms and 1 or 2 heteroatoms independently selected from    N,N(H), and N(C₁-C₆ alkyl), and 5- and 6-membered heteroaryl are    monocyclic rings; and 9- and 10-membered heteroaryl are 6,5-fused    and 6,6-fused bicyclic rings, respectively, wherein at least 1 of    the 2 fused rings of a bicyclic ring is aromatic, and wherein when    the O and S atoms both are present, the O and S atoms are not bonded    to each other;-   wherein with any (C₁-C₆ alkyl)₂-N group, the C₁-C₆ alkyl groups may    be optionally taken together with the nitrogen atom to which they    are attached to form a 5- or 6-membered heterocycloalkyl; and-   wherein each group and each substituent recited above is    independently selected.

Another aspect of this invention is the compound of Formula Ia, or apharmaceutically acceptable salt thereof, wherein S, T, U, and W areeach CH or one of S, T, U, and W is N and the other three of S, T, U,and W are each CH, and V is selected from the groups:

wherein X is O, S, or N(H).

Another aspect of this invention is the compound of Formula Ia, or apharmaceutically acceptable salt thereof, wherein S, T, U, and W areeach CH or one of S, T, U, and W is N and the other three of S, T, U,and W are each CH, and Q is C≡C or N(R⁶)C(O).

Another aspect of this invention is the compound of Formula Ia, or apharmaceutically acceptable salt thereof, wherein S, T, U, and W areeach CH or one of S, T, U, and W is N and the other three of S, T, U,and W are each CH, and Q is selected from:

wherein X is O, S, or N(H).

Another aspect of this invention is the compound of Formula Ia, or apharmaceutically acceptable salt thereof, wherein S, T, U, and W areeach CH or one of S, T, U, and W is N and the other three of S, T, U,and W are each CH, and each of R¹ and R² are independently selectedfrom:

Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);

Phenyl-(C₁-C₆ alkylenyl);

Substituted phenyl-(C₁-C₆ alkylenyl);

5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and

Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl);

-   wherein each heteroaryl contains carbon atoms and from 1 to 4    heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆    alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic    rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused    bicyclic rings, respectively, wherein at least 1 of the 2 fused    rings of a bicyclic ring is aromatic, and wherein when the O and S    atoms both are present, the O and S atoms are not bonded to each    other; and-   wherein each group and each substituent is independently selected.

Another aspect of this invention is the compound of Formula Ia ofFormulas IIa, III, IV, V, VI, VII, or VIII

or a pharmaceutically acceptable salt thereof,

-   -   wherein T is CH or N, X is O, S, or N(H), and each of R¹ and R²        are independently selected from:    -   Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl);    -   Phenyl-(C₁-C₆ alkylenyl);    -   Substituted phenyl-(C₁-C₆ alkylenyl);    -   5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); and    -   Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C₁-C₆        alkylenyl);    -   wherein each heteroaryl contains carbon atoms and from 1 to 4        heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1        N(C₁-C₆ alkyl), and 4 N, and 5- and 6-membered heteroaryl are        monocyclic rings and 9- and 10-membered heteroaryl are 6,5-fused        and 6,6-fused bicyclic rings, respectively, wherein at least 1        of the 2 fused rings of a bicyclic ring is aromatic, and wherein        when the O and S atoms both are present, the O and S atoms are        not bonded to each other; and    -   wherein each group and each substituent is independently        selected.

Another aspect of this invention is a compound of Formula Ia selectedfrom:

-   4-(5-{3-[5-(4-Chloro-phenyl)-thiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid (B5); and-   4-(5-{3-[5-(4-Chloro-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid; or

a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds defined by Formula I

or a pharmaceutically acceptable salt thereof,wherein R¹, Q, S, T, U, V, and R² are as defined above.

The invention also provides pharmaceutical compositions comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof, asdefined above, together with a pharmaceutically acceptable carrier,diluent, or excipient.

The invention also provides methods of inhibiting an MMP-13 enzyme in ananimal, comprising administering to the animal a compound of Formula I,or a pharmaceutically acceptable salt thereof.

The invention also provides methods of treating a disease mediated by anMMP-13 enzyme in a patient, comprising administering to the patient acompound of Formula I, or a pharmaceutically acceptable salt thereof,either alone or in a pharmaceutical composition.

The invention also provides methods of treating diseases such as heartdisease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritisother than osteo- or rheumatoid arthritis, cardiac insufficiency,inflammatory bowel disease, heart failure, age-related maculardegeneration, chronic obstructive pulmonary disease, asthma, periodontaldiseases, psoriasis, atherosclerosis, and osteoporosis in a patient,comprising administering to the patient a compound of Formula I, or apharmaceutically acceptable salt thereof, either alone or in apharmaceutical composition.

The invention also provides combinations, comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof, together withanother pharmaceutically active component as described.

As seen above, the groups of Formula I include “C₁-C₆ alkyl” groups.C₁-C₆ alkyl groups are straight and branched carbon chains having from 1to 6 carbon atoms. Examples of C₁-C₆ alkyl groups include methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl,2-pentyl, 2,2-dimethylpropyl, and 1-hexyl.

The phrase “substituted C₁-C₆ alkyl” means a C₁-C₆ alkyl group asdefined above that is substituted with from 1 to 4 substituentsindependently selected from the list above. Illustrative examples ofsubstituted C₁-C₆ alkyl groups include CH₂OH, CF₂OH, CH₂C(CH₃)₂CO₂CH₃,CF₃, C(O)CF₃, C(O)—CH₃, (CH₂)₄—S—CH₃, CH(CO₂H)CH₂CH₂C(O)NMe₂,(CH₂)₅NH—C(O)—NH₂, CH₂—CH₂—C(H)-(4-fluorophenyl), CH(OCH₃)CH₂CH₃,CH₂SO₂NH₂, and CH(CH₃)CH₂CH₂OC(O)CH₃.

The term “C₂-C₆ alkenyl” means a straight or branched, unsubstitutedhydrocarbon group having from 2 to 6 carbon atoms and 1 or 2carbon-carbon double bonds, and include allenyl groups. Typical examplesof C₂-C₆ alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl,2-propen-1-yl, 1-buten-3-yl, 2-penten-2-yl, and 1-hexen-6-yl.

The phrase “substituted C₂-C₆ alkenyl” means a C₂-C₆ alkenyl as definedabove, which is substituted with from 1 to 4 substituents independentlyselected from the list above. Illustrative examples of substituted C₂-C₆alkenyl groups include C(H)═C(H)CH₂OH, CH═CF₂, CH₂C(H)═C(H)—(CH₂)₂CF₂OH,CH₂C(═CH₂)CO₂CH₃, C(H)═C(H)—CF₃, CH₂—CH₂—C(H)═C(H)—C(O)—CH₃,C(H)═C(CH₃)—S—CH₃, C(H)═C(H)—C(H)═C(CH₃)—CO₂Me, and C(H)═C═C(H)OC(O)CH₃.

The term “C₂-C₆ alkynyl” means a straight or branched, unsubstitutedhydrocarbon group having from 2 to 6 carbon atoms and 1 or 2carbon-carbon triple bonds. Typical examples of C₂-C₆ alkynyl groupsinclude ethenyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-3-yl,2-pentyn-1-yl, and 1-hexyn-6-yl.

The phrase “substituted C₂-C₆ alkynyl” means a C₂-C₆ alkynyl as definedabove, which is substituted with from 1 to 4 substituents independentlyselected from the list above. Illustrative examples of substituted C₂-C₆alkynyl groups include C≡CCH₂OH, C≡CF, CH₂C≡C—(CH₂)₂CF₂OH,C≡C—CH₂CO₂CH₃, CH₂C≡C—CF₃, CH₂—CH₂—C≡C—C(O)—CH₃, C≡C—S—CH₃, andC≡C—C(O)OC(O)CH₃.

The term “C₃-C₆ cycloalkyl” means an unsubstituted cyclic hydrocarbongroup having from 3 to 6 carbon atoms. C₃-C₆ cycloalkyl may optionallycontain one carbon-carbon double bond. The group C₃-C₆ cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl,cyclopenten-4-yl, and cyclohexyl.

The phrase “substituted C₃-C₆ cycloalkyl” means a C₃-C₆ cycloalkyl asdefined above, which is substituted with from 1 to 4 substituentsindependently selected from the list above. Illustrative examples ofsubstituted C₃-C₆ cycloalkyl groups include 1-hydroxy-cyclopropyl,cyclobutanon-3-yl, 3-(3-phenyl-ureido)-cyclopent-1-yl, and4-carboxy-cyclohexyl.

The phrase “3- to 6-membered heterocycloalkyl” means an unsubstitutedsaturated cyclic group having carbon atoms and 1 or 2 heteroatomsindependently selected from 2 O, 1 S, 1 S(O), 1 S(O)₂, 1 N, 2 N(H), and2 N(C₁-C₆ alkyl), wherein when two O atoms or one O atom and one S atomare present, the two O atoms or one O atom and one S atom are not bondedto each other. Optionally, a 3- to 6-membered heterocycloalkyl maycontain one carbon-carbon or carbon-nitrogen double bond. Illustrativeexamples of 3- to 6-membered heterocycloalkyl includes aziridin-1-yl,1-oxa-cyclobutan-2-yl, tetrahyrdofuran-3-yl, morpholin-4-yl,2-thiacyclohex-1-yl, 2-oxo-2-thiacyclohe-1-yl,2,2-dioxo-2-thiacyclohex-1-yl, and 4-methyl-piperazin-2-yl.

The phrase “substituted 3- to 6-membered heterocycloalkyl” means a 3- to6-membered heterocycloalkyl as defined above, which is substituted withfrom 1 to 4 substituents independently selected from the list above.Illustrative examples of substituted 3- to 6-membered heterocycloalkylinclude 2-hydroxy-aziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl,2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, and1-cyclopropyl-4-methyl-piperazin-2-yl.

The term “HO—C(═O)—(C₃-C₆ cycloalkylen-1-yl)” means a radical group offormula (A)

The term “C₁-C₆ alkylenyl” means a saturated hydrocarbon diradical thatis straight or branched and has from 1 to 6 carbon atoms. C₁-C₆alkylenyl having from 2 to 6 carbon atoms may optionally contain onecarbon-carbon double bond. Illustrative examples of C₁-C₆ alkylenylinclude CH₂, CH₂CH₂, C(CH₃)H, C(H)(CH₃)CH₂CH₂, and CH₂C(H)═C(H)CH₂.Analogously, C₁-C₃ alkylenyl means a saturated hydrocarbon diradicalthat is straight or branched and has from 1 to 3 carbon atoms.

The phrase “C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl)” means a C₃-C₆cycloalkyl, as defined above, bonded through a C₁-C₆ alkylenyl, asdefined above.

The phrase “Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl)-(C₁-C₆alkylenyl)” means a substituted C₃-C₆ cycloalkyl, as defined above,bonded through a C₁-C₆ alkylenyl, as defined above.

The phrase “3- to 6-membered heterocycloalkyl-(C₁-C₆ alkylenyl)” means a3- to 6-membered heterocycloalkyl, as defined above, bonded through aC₁-C₆ alkylenyl, as defined above.

The phrase “Substituted 3- to 6-membered heterocycloalkyl-(C₁-C₆alkylenyl)” means a substituted 3- to 6-membered heterocycloalkyl, asdefined above, bonded through a C₁-C₆ alkylenyl, as defined above.

The phrase “Phenyl-(C₁-C₆ alkylenyl)” means a phenyl group bondedthrough a C₁-C₆ alkylenyl diradical, wherein C₁-C₆ alkylenyl is asdefined above. Illustrative examples of phenyl-(C₁-C₆ alkylenyl) includebenzyl, 2-phenylethyl, 1-phenyl-prop-1-yl, and 3-phenyl-pentyl.

The phrase “Substituted phenyl-(C₁-C₆ alkylenyl)” means a phenyl-(C₁-C₆alkylenyl) as defined above, which is substituted on phenyl and/or C₁-C₆alkylenyl with from 1 to 4 substituents independently selected from thelist above. Illustrative examples of substituted phenyl-(C₁-C₆alkylenyl) include 4-fluoro-phenylmethyl, 2-(4-carboxy-phenyl)-ethyl,1-(2,4-dimethoxy-phenyl)-2-oxo-propyl, and 1-phenyl-5,5-difluoropentyl.

The term “naphthyl” includes 1-naphthyl and 2-napthyl.

The phrase “Naphthyl-(C₁-C₆ alkylenyl)” means a naphthyl group asdefined above bonded through a C₁-C₆ alkylenyl diradical, wherein C₁-C₆alkylenyl is as defined above. Illustrative examples of naphthyl-(C₁-C₆alkylenyl) include naphth-1-ylmethyl, 2-(naphth-1-yl)ethyl, and3-(naphth-2-yl)-1-pentyl.

The phrase “Substituted naphthyl-(C₁-C₆ alkylenyl)” means anaphthyl-(C₁-C₆ alkylenyl) as defined above, which is substituted onnaphthyl and/or C₁-C₆ alkylenyl with from 1 to 4 substituentsindependently selected from the list above. Illustrative examples ofsubstituted phenyl-(C₁-C₆ alkylenyl) include4-fluoro-(naphth-1-yl)methyl, 2-(4-carboxy-(naphth-1-yl))-ethyl,1-(2,4-dimethoxy-(naphth-1-yl))-2-oxo-propyl, and1-(naphth-2-yl)-5,5-difluoropentyl.

The phrase “5-, 6-, 9-, and 10-membered heteroaryl” means a 5-membered,monocyclic heteroaryl, a 6-membered, monocyclic heteroaryl, a9-membered, 6,5-fused bicyclic heteroaryl, or a 10-membered, 6,6-fusedbicyclic heteroaryl, having carbon atoms and from 1 to 4 heteroatomsindependently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆ alkyl), and 4 N,wherein at least one of the 2 fused rings is aromatic, and wherein whenthe O and S atoms both are present, the O and S atoms are not bonded toeach other, which are as defined below:

(i) The phrase “5-membered, monocyclic heteroaryl” means a 5-membered,monocyclic, aromatic ring group as defined above having carbon atoms andfrom 1 to 4 heteroatoms selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆alkyl), and 4 N. Illustrative examples of a 5-membered, monocyclicheteroaryl include thiophen-2-yl, furan-2-yl, pyrrol-3-yl, pyrrol-1-yl,imidazol-4-yl, isoxazol-3-yl, oxazol-2-yl, thiazol-4-yl, tetrazol-1-yl,1,2,4-oxadiazol-3-yl, 1,2,4-triazol-1-yl, and pyrazol-3-yl;

(ii) The phrase “6-membered, monocyclic heteroaryl” means a 6-membered,monocyclic, aromatic ring group as defined above having carbon atoms and1 or 2 N. Illustrative examples of a 6-membered, monocyclic heteroarylinclude pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, andpyrazin-2-yl;

(iii) The phrase “9-membered, 6,5-fused bicyclic heteroaryl” means a9-membered aromatic, fused-bicyclic ring group as defined above havingcarbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 N(H),1 N(C₁-C₆ alkyl), and 4 N. Illustrative examples of a 9-membered,fused-bicyclic heteroaryl include indol-2-yl, indol-6-yl,iso-indol-2-yl, benzimidazol-2-yl, benzimidazol-1-yl, benztriazol-1-yl,benztriazol-5-yl, benzoxazol-2-yl, benzothiophen-5-yl, benzofuran-3-yl,and indan-1-yl; and

(iv) The phrase “10-membered, 6,5-fused bicyclic heteroaryl” means a10-membered aromatic, fused-bicyclic ring group as defined above havingcarbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 N(H),1 N(C₁-C₆ alkyl), and 4 N. Illustrative examples of a 10-membered,fused-bicyclic heteroaryl include quinolin-2-yl, isoquinolin-7-yl, andbenzopyrimidin-2-yl.

The phrase “substituted 5-, 6-, 9-, and 10-membered heteroaryl” means a5-, 6-, 9-, and 10-membered heteroaryl as defined above, which issubstituted on a carbon (CH) atom and/or nitrogen [N(H)] atom in thecase of 5-, 9-, and 10-membered heteroaryl, with from 1 to 4substituents independently selected from the list above.

Illustrative examples of substituted 5-membered, monocyclic heteroarylgroups include 2-hydroxy-oxoazol-4-yl, 5-chloro-thiophen-2-yl,1-methylimidazol-5-yl, 1-propyl-pyrrol-2-yl, 1-acetyl-pyrazol-4-yl,1-methyl-1,2,4-triazol-3-yl, and 2-hexyl-tetrazol-5-yl.

Illustrative examples of substituted 6-membered, monocyclic heteroarylgroups include 4-acetyl-pyridin-2-yl, 3-fluoro-pyridin-4-yl,5-carboxy-pyrimidin-2-yl, 6-tertiary butyl-pyridazin-4-yl,5-hdyroxymethyl-pyrazin-2-yl, and 1H-pyridin-4-one-1-yl.

Illustrative examples of substituted 9-membered, fused-bicyclicheteroaryl include 3-(2-aminomethyl)-indol-2-yl, 2-carboxy-indol-6-yl,1-(methanesulfonyl)-iso-indol-2-yl,5-trifluoromethyl-6,7-difluoro-4-hydroxymethyl-benzimidazol-2-yl,4-(3-methylureido)-2-cyano-benzimidazol-1-yl, 1-methylbenzimidazol-6-yl,1-acetylbenztriazol-7-yl, 1-methanesulfonyl-indol-3-yl,1-cyano-6-aza-indol-5-yl, and1-(2,6-dichlorophenylmethyl)-benzpyrazol-3-yl.

Illustrative examples of substituted 10-membered, fused-bicyclicheteroaryl include 5,7-dichloro-quinolin-2-yl,isoquinolin-7-yl-1-carboxylic acid ethyl ester, and3-bromo-benzopyrimidin-2-yl.

The phrase “5-membered heteroarylenyl” means a 5-membered, monocyclic,aromatic ring diradical group having carbon atoms and from 1 to 4heteroatoms selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆ alkyl), and 4 N.Optionally, heteroarylenyl may be unsubstituted or substituted on acarbon atom (CH) or nitrogen atom [N(H)] with 1 substituent selectedfrom fluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetylIllustrative examples of a 5-membered heteroarylenyl includethiophen-2,5-diyl, furan-2,3-di-yl, pyrrol-1,3-di-yl, imidazol-1,4-diyl,tetrazol-2,5-diyl, tetrazol-1,5-dicyl, oxadiazol-3,5-diyl,thiazol-2,4-diyl, and pyrazol-1,3-diyl.

Preferred substituents for substituted phenyl, substituted naphthyl(i.e., substituted 1-naphthyl or substituted 2-naphthyl), and preferredsubstituents at carbon atoms for substituted 5-membered, monocyclicheteroaryl, substituted 6-membered, monocyclic heteroaryl, andsubstituted 9- or 10-membered, fused-bicyclic heteroaryl are C₁-C₄alkyl, halo, OH, O—C₁-C₄ alkyl, oxo (“═O”), 1,2-methylenedioxy, CN, NO₂,N₃, NH₂, N(H)CH₃, N(CH₃)₂, C(O)CH₃, OC(O)—C₁-C₄ alkyl, C(O)—H, CO₂H,CO₂—(C₁-C₄ alkyl), C(O)—N(H)OH, C(O)NH₂, C(O)NHMe, C(O)N(Me)₂,NHC(O)CH₃, N(H)C(O)NH₂, SH, S—C₁-C₄ alkyl, C—CH, C(═NOH)—H, C(═NOH)—CH₃,CH₂OH, CH₂NH₂, CH₂N(H)CH₃, CH₂N(CH₃)₂, C(H)F—OH, CF₂—OH, S(O)₂NH₂,S(O)₂N(H)CH₃, S(O)₂N(CH₃)₂, S(O)—CH₃, S(O)₂CH₃, S(O)₂CF₃, or NHS(O)₂CH₃.

Especially preferred substituents are 1,2-methylenedioxy, methoxy,ethoxy, —O—C(O)CH₃, carboxy, carbomethoxy, and carboethoxy.

The term “1,2-methylenedioxy” means the diradical group —O—CH₂—O—,wherein the substituent 1,2-methylenedioxy is bonded to adjacent carbonatoms of the group which is substituted to form a 5-membered ring.Illustrative examples of groups substituted by 1,2-methylenedioxyinclude 1,3-benzoxazol-5-yl of formula B

which is a phenyl group substituted by 1,2-methylenedioxy.

A fused-bicyclic group is a group wherein two ring systems share two,and only two, atoms.

It should be appreciated that the groups heteroaryl or heterocycloalkylmay not contain two ring atoms bonded to each other which atoms areoxygen and/or sulfur atoms.

The term “oxo” means ═O. Oxo is attached at a carbon atom unlessotherwise noted. Oxo, together with the carbon atom to which it isattached forms a carbonyl group (i.e., C═O).

The term “heteroatom” includes O, S, S(O), S(O)₂, N,N(H), and N(C₁-C₆alkyl).

The term “halo” includes fluoro, chloro, bromo, and iodo.

The term “amino” means NH₂.

The phrase “two adjacent, substantially sp² carbon atoms” means carbonatoms that comprise a carbon-carbon double bond that is capable of beingsubstituted on each carbon atom, wherein the carbon-carbon double bondis contained in an aromatic or nonaromatic, cyclic or acyclic, orcarbocyclic or heterocyclic group.

The phrase “tertiary organic amine” means a trisubstituted nitrogengroup wherein the 3 substituents are independently selected from C₁-C₁₂alkyl, C₃-C₁₂ cycloalkyl, benzyl, or wherein two of the substituents aretaken together with the nitrogen atom to which they are bonded to form a5- or 6-membered, monocyclic heterocycle containing one nitrogen atomand carbon atoms, and the third substituent is selected from C₁-C₁₂alkyl and benzyl, or wherein the three substituents are taken togetherwith the nitrogen atom to which they are bonded to form a 7- to12-membered bicyclic heterocycle containing 1 or 2 nitrogen atoms andcarbon atoms, and optionally a C═N double bond when 2 nitrogen atoms arepresent. Illustrative examples of tertiary organic amine includetriethylamine, diisopropylethylamine, benzyl diethylamino,dicyclohexylmethyl-amine, 1,8-diazabicycle[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (TED), and1,5-diazabicycle[4.3.0]non-5-ene.

The phrase “pharmaceutical composition” means a composition suitable foradministration in medical or veterinary use.

The term “admixed” and the phrase “in admixture” are synonymous and meanin a state of being in a homogeneous or heterogeneous mixture. Preferredis a homogeneous mixture.

The term “patient” means a mammal. Preferred patients are humans, cats,dogs, cows, horses, pigs, and sheep.

The term “animal” means a mammal, as defined above. Preferred animalsinclude humans, cats, dogs, horses, pigs, sheep, cows, monkeys, rats,mice, guinea pigs, and rabbits.

The term “mammal” includes humans, companion animals such as cats anddogs, primates such as monkeys and chimpanzees, and livestock animalssuch as horses, cows, pigs, and sheep.

The phrase “livestock animals” as used herein refers to domesticatedquadrupeds, which includes those being raised for meat and variousbyproducts, e.g., a bovine animal including cattle and other members ofthe genus Bos, a porcine animal including domestic swine and othermembers of the genus Sus, an ovine animal including sheep and othermembers of the genus Ovis, domestic goats and other members of the genusCapra; domesticated quadrupeds being raised for specialized tasks suchas use as a beast of burden, e.g., an equine animal including domestichorses and other members of the family Equidae, genus Equus, or forsearching and sentinel duty, e.g., a canine animal including domesticdogs and other members of the genus Canis; and domesticated quadrupedsbeing raised primarily for recreational purposes, e.g., members of Equusand Canis, as well as a feline animal including domestic cats and othermembers of the family Felidae, genus Felis.

The phrase “anticancer effective amount” means an amount of inventioncompound, or a pharmaceutically acceptable salt thereof, or a tautomerthereof, sufficient to inhibit, halt, or cause regression of the cancerbeing treated in a particular patient or patient population. For examplein humans or other mammals, an anticancer effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular cancerand patient being treated.

The phrase “anti-arthritic effective amount” means an amount ofinvention compound, or a pharmaceutically acceptable salt thereof, or atautomer thereof, sufficient to inhibit, halt, or cause regression ofthe arthritis being treated in a particular patient or patientpopulation. For example in humans or other mammals, an anti-arthriticeffective amount can be determined experimentally in a laboratory orclinical setting, or may be the amount required by the guidelines of theUnited States Food and Drug Administration, or equivalent foreignagency, for the particular arthritis and patient being treated.

The phrase “MMP-13 inhibiting amount” means an amount of inventioncompound, or a pharmaceutically acceptable salt thereof, or a tautomerthereof, sufficient to inhibit an enzyme matrix metalloproteinase-13,including a truncated form thereof, including a catalytic domainthereof, in a particular animal or animal population. For example in ahuman or other mammal, an MMP-13 inhibiting amount can be determinedexperimentally in a laboratory or clinical setting, or may be the amountrequired by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular MMP-13enzyme and patient being treated.

It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration, is within the level ofordinary skill in the pharmaceutical and medical arts, and is describedbelow.

The phrases “effective amount” and “therapeutically effective amount”are synonymous and mean an amount of a compound of the presentinvention, a pharmaceutically acceptable salt thereof, or a solvatethereof, sufficient to effect an improvement of the condition beingtreated when administered to a patient suffering from a disease that ismediated by MMP-13 and optionally from 0 to 12 additional MMP enzymes.

The term “tautomer” means a form of invention compound existing in astate of equilibrium with an isomeric form of the invention compound,wherein the invention compound is able to react according to either formby virtue of the ability of the forms to interconvert by isomerizationin situ, including in a reaction mixture, in an in vitro biologicalassay, or in vivo.

The term “(E)” means entgegen, and designates that the conformationabout the double bond to which the term refers is the conformationhaving the two higher-ranking substituent groups, as determinedaccording to the Cahn-Ingold-Prelog ranking system, on opposite sides ofthe double bond. An (E) double bond is illustrated below by the compoundof Formula (W)

wherein the two higher-ranking substituents are groups A and D.

The term “(Z)” means zusammen, and designates that the conformationabout the double bond to which the term refers is the conformationhaving the two higher-ranking substituent groups, as determinedaccording to the Cahn-Ingold-Prelog ranking system, on the same side ofthe double bond. A (Z) double bond is illustrated below by the compoundof Formula (X)

wherein the two higher-ranking substituents are groups A and D.

It should be appreciated that the S1′ site of MMP-13 was previouslythought to be a grossly linear channel which contained an opening at thetop that allowed an amino acid side chain from a substrate molecule toenter during binding, and was closed at the bottom. Applicants hasdiscovered that the S1′ site is actually composed of an S1′ channelangularly connected to a newly discovered pocket which applicant callsthe S1″ site. The S1″ site is open to solvent at the bottom, which canexpose a functional group of Applicants' invention compounds to solvent.For illustrative purposes, the S1′ site of the MMP-13 enzyme can now bethought of as being like a sock with a hole in the toes, wherein the S1′channel is the region from approximately the opening to the ankle, andthe S1″ site is the foot region below the ankle, which foot region isangularly connected to the ankle region.

More particularly, the S1′ channel is a specific part of the S1′ siteand is formed largely by Leu218, Val219, His222 and by residues fromLeu239 to Tyr244. The S1″ binding site which has been newly discoveredis defined by residues from Tyr246 to Pro255. The S1″ site contains atleast two hydrogen bond donors and aromatic groups which interact withan invention compound.

Without wishing to be bound by any particular theory, the inventorsbelieve that the S1″ site could be a recognition site for triple helixcollagen, the natural substrate for MMP-13. It is possible that theconformation of the S1″ site is modified only when an appropriatecompound binds to MMP-13, thereby interfering with the collagenrecognition process. This newly discovered pattern of binding offers thepossibility of greater selectivity than what is achievable with thebinding pattern of known selective inhibitors of MMP-13, wherein theknown binding pattern requires ligation of the catalytic zinc atom atthe active site and occupation the S1′ channel, but not the S1″ site.

The term “Thour245” means threonine 245 of an MMP-13 enzyme.

The term “Thour247” means threonine 247 of an MMP-13 enzyme.

The term “Met253” means methionine 253 of an MMP-13 enzyme.

The term “His251” means histidine 251 of an MMP-13 enzyme.

It should be appreciated that the matrix metalloproteinases include, butare not limited to, the following enzymes: MMP-1, also known asinterstitial collagenase, collagenase-1, or fibroblast-type collagenase;

MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;

MMP-3, also known as stromelysin or stromelysin-1;

MMP-7, also known as matrilysin or PUMP-1;

MMP-8, also known as collagenase-2, neutrophil collagenase orpolymorphonuclear-type (“PMN-type”) collagenase;

MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;

MMP-10, also known as stromelysin-2;

MMP-11, also known as stromelysin-3;

MMP-12, also known as metalloelastase;

MMP-13, also known as collagenase-3;

MMP-14, also known as membrane-type (“MT”) 1-MMP or MT1-MMP;

MMP-15, also known as MT2-MMP;

MMP-16, also known as MT3-MMP;

MMP-17, also known as MT4-MMP;

MMP-18; and

MMP-19.

Other known MMPs include MMP-26 (Matrilysin-2).

For the purposes of this invention, the term “arthritis”, which issynonymous with the phrase “arthritic condition”, includesosteoarthritis, rheumatoid arthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis, and psoriatic arthritis. An allosteric inhibitor ofMMP-13 having an anti-arthritic effect is a compound as defined abovethat inhibits the progress, prevents further progress, or reversesprogression, in part or in whole, of any one or more symptoms of any oneof the arthritic diseases and disorders listed above.

The term “IC₅₀” means the concentration of a compound, usually expressedas micromolar or nanomolar, required to inhibit an enzyme's catalyticactivity by 50%.

The term “ED₄₀” means the concentration of a compound, usually expressedas micromolar or nanomolar, required to treat a disease in about 40% ofa patient group.

The term “ED₃₀” means the concentration of a compound, usually expressedas micromolar or nanomolar, required to treat a disease in 30% of apatient group.

The phrase “pharmaceutical composition” means a composition suitable foradministration in medical or veterinary use.

The term “admixed” and the phrase “in admixture” are synonymous and meanin a state of being in a homogeneous or heterogeneous mixture. Preferredis a homogeneous mixture.

As used herein, the phrase “cartilage damage” means a disorder ofhyaline cartilage and subchondral bone characterized by hypertrophy oftissues in and around the involved joints, which may or may not beaccompanied by deterioration of hyaline cartilage surface.

The phrase “treating”, which is related to the terms “treat” and“treated”, means administration of an invention combination as definedabove that inhibits the progress, prevents further progress, or reversesprogression, in part or in whole, of any one or more symptoms of any oneof the diseases and disorders listed above.

The phrase “invention compound” means a compound of Formula I, or apharmaceutically acceptable salt thereof, as fully defined above.

The term “nontoxic” means the efficacious dose is 10 times or greaterthan the dose at which a toxic effect is observed in 10% or more of apatient population.

The term “celecoxib” means the compound named4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-benzenesulfonamide.Celecoxib is a selective cyclooxygenase-2 (“COX-2”) inhibitor currentlyapproved by the FDA for the treatment of osteoarthritis, rheumatoidarthritis, and Polyposis-familial adenomatus. Celecoxib is marketedunder the tradename “Celebrex”. Celecoxib is currently in clinicaltrials for the treatment of bladder cancer, chemopreventative-lungcancer, and post-operative pain, and is registered for the treatment ofdysmenorrhea. Celecoxib has the structure drawn below:

The term “valdecoxib” means the compound named4-(5-methyl-3-phenyl-4-isoxazolyl)-benzenesulfonamide. Valdecoxib is aselective COX-2 inhibitor that has been approved by the FDA for treatingosteoarthritis, rheumatoid arthritis, dysmenorrhea, and general pain,and is marketed under the tradename “Bextra”. Valdecoxib is in clinicaltrials for the treatment of migraine. Valdecoxib has the structure drawnbelow:

It should be appreciated that COX-2 is also known as prostaglandinsynthase-2 and prostaglandin PGH₂ synthase.

A selective inhibitor of COX-2 means compounds that inhibit COX-2selectively versus COX-1 such that a ratio of IC₅₀ for a compound withCOX-1 divided by a ratio of IC₅₀ for the compound with COX-2 is greaterthan, or equal to, 5, where the ratios are determined in one or moreassays. All that is required to determine whether a compound is aselective COX-2 inhibitor is to assay a compound in one of a number ofwell know assays in the art.

The term “NSAID” is an acronym for the phrase “nonsteroidalanti-inflammatory drug”, which means any compound which inhibitscyclooxygenase-1 (“COX-1”) and cyclooxygenase-2. Most NSAIDs fall withinone of the following five structural classes: (1) propionic acidderivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, andketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac;(3) fenamic acid derivatives, such as mefenamic acid and meclofenamicacid; (4) biphenylcarboxylic acid derivatives, such as diflunisal andflufenisal; and (5) oxicams, such as piroxim, peroxicam, sudoxicam, andisoxicam. Other useful NSAIDs include aspirin, acetominophen,indomethacin, and phenylbutazone. Selective inhibitors ofcyclooxygenase-2 as described above may be considered to be NSAIDs also.

The term “drugs”, which is synonymous with the phrases “activecomponents”, “active compounds”, and “active ingredients”, includescelecoxib, or a pharmaceutically acceptable salt thereof, valdecoxib, ora pharmaceutically acceptable salt thereof, and an allosteric inhibitorof MMP-13, and may further include one or two of the other therapeuticagents described above.

It should be appreciated that in the Summary of the Invention above, theterm “Embodiment” refers to an aspect of this invention. The Embodimentsin the Summary of the Invention are numbered for ease of referral.

The compounds of Formula I, or pharmaceutically acceptable saltsthereof, or tautomers thereof, include compounds which are inventioncompounds. An allosteric inhibitor of MMP-13 is any compound of FormulaI that binds allosterically into the S1′ site of the MMP-13 enzyme,including the S1′ channel, and a newly discovered S1″ site, withoutligating, coordinating, or binding the catalytic zinc of the MMP-13.

An invention compound that is an allosteric inhibitor of MMP-13 may bereadily identified by one of ordinary skill in the pharmaceutical ormedical arts by assaying an alkyne test compound for inhibition ofMMP-13 as described below in Biological Methods 1 or 2, and forallosteric inhibition of MMP-13 by assaying the test invention compoundfor inhibition of MMP-13 in the presence of an inhibitor to thecatalytic zinc of MMP-13 as described below in Biological Methods 3 or4.

Further, an invention compound having an anti-inflammatory, ananalgesic, anti-arthritic, or a cartilage damage inhibiting effect, orany combination of these effects, may be readily identified by one ofordinary skill in the pharmaceutical or medical arts by assaying theinvention compound in any number of well known assays for measuringdetermining the invention compound's effects on cartilage damage,arthritis, inflammation, or pain. These assays include in vitro assaysthat utilize cartilage samples and in vivo assays in whole animals thatmeasure cartilage degradation, inhibition of inflammation, or painalleviation.

For example with regard to assaying cartilage damage in vitro, an amountof an invention compound or control vehicle may be administered with acartilage damaging agent to cartilage, and the cartilage damageinhibiting effects in both tests studied by gross examination orhistopathologic examination of the cartilage, or by measurement ofbiological markers of cartilage damage such as, for example,proteoglycan content or hydroxyproline content. Further, in vivo assaysto assay cartilage damage may be performed as follows: an amount of aninvention compound or control vehicle may be administered with acartilage damaging agent to an animal, and the effects of the inventioncompound being assayed on cartilage in the animal may be evaluated bygross examination or histopathologic examination of the cartilage, byobservation of the effects in an acute model on functional limitationsof the affected joint that result from cartilage damage, or bymeasurement of biological markers of cartilage damage such as, forexample, proteoglycan content or hydroxyproline content.

Several methods of identifying an invention compound with cartilagedamage inhibiting properties are described below. The amount to beadministered in an assay is dependent upon the particular assayemployed, but in any event is not higher than the well known maximumamount of a compound that the particular assay can effectivelyaccommodate.

Similarly, invention compounds having pain-alleviating properties may beidentified using any one of a number of in vivo animal models of pain.

Still similarly, invention compounds having anti-inflammatory propertiesmay be identified using any one of a number of in vivo animal models ofinflammation. For example, for an example of inflammation models, seeU.S. Pat. No. 6,329,429, which is incorporated herein by reference.

Still similarly, invention compounds having anti-arthritic propertiesmay be identified using any one of a number of in vivo animal models ofarthritis. For example, for an example of arthritis models, see alsoU.S. Pat. No. 6,329,429.

Other mammalian diseases and disorders which are treatable byadministration of an invention combination alone, or contained in apharmaceutical composition as defined below, include: fever (includingrheumatic fever and fever associated with influenza and other viralinfections), common cold, dysmenorrhea, menstrual cramps, inflammatorybowel disease, Crohn's disease, emphysema, acute respiratory distresssyndrome, asthma, bronchitis, chronic obstructive pulmonary disease,Alzheimer's disease, organ transplant toxicity, cachexia, allergicreactions, allergic contact hypersensitivity, cancer (such as solidtumor cancer including colon cancer, breast cancer, lung cancer andprostrate cancer; hematopoietic malignancies including leukemias andlymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiaradenomatous polyposis), tissue ulceration, peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock), epilepsy, convulsions, and septic shock.

Other aspects of the present invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, that are ≧10, ≧20, ≧50, ≧100,or ≧1000 times more potent versus MMP-13 than versus at least two of anyother MMP enzyme or TACE.

Still other aspects of the present invention are compounds of Formula I,or a pharmaceutically acceptable salt thereof, that are selectiveinhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, orversus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes.

It should be appreciated that selectivity of a compound of Formula I, ora pharmaceutically acceptable salt thereof, is a multidimensionalcharacteristic that includes the number of other MMP enzymes and TACEover which selectivity for MMP-13 inhibition is present and the degreeof selectivity of inhibition of MMP-13 over another particular MMP orTACE, as measured by, for example, the IC₅₀ in micromolar concentrationof the compound for the inhibition of the other MMP enzyme or TACEdivided by the IC₅₀ in micromolar concentration of the compound for theinhibition of MMP-13.

As discussed above, one aspect of the present invention is novelcompounds that are selective inhibitors of the enzyme MMP-13. Aselective inhibitor of MMP-13, as used in the present invention, is acompound that is ≧5× more potent in vitro versus MMP-13 than versus atleast one other matrix metalloproteinase enzyme such as, for example,MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, or MMP-14, or versus tumornecrosis factor alpha convertase (“TACE”). A preferred aspect of thepresent invention is novel compounds that are selective inhibitors ofMMP-13 versus MMP-1.

The invention provides a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, which has an IC₅₀ with any MMP enzyme that isless than or equal to 50 micromolar. Preferred are compounds of FormulaI, or a pharmaceutically acceptable salt thereof, which have an IC₅₀with a human full-length MMP-13 (“hMMP-13FL”) or a human MMP-13catalytic domain (“hMMP-13CD”) that is less than or equal to 50micromolar. More preferred are compounds of Formula I, or apharmaceutically acceptable salt thereof, which have an IC₅₀ with ahuman full-length MMP-13 (“hMMP-13FL”) or a human MMP-13 catalyticdomain (“hMMP-13CD”) that is less than or equal to 10 micromolar.Examples of biological methods useful for determining IC₅₀s for theinvention compounds with an MMP are described below in BiologicalMethods 1 to 4. Any compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or any form thereof as defined above, that doesnot have an IC₅₀ with any MMP enzyme that is less than, or equal to, 10micromolar is excluded from this invention.

Some of the invention compounds are capable of further forming nontoxicpharmaceutically acceptable salts, including, but not limited to, acidaddition and/or base salts. The acid addition salts are formed frombasic invention compounds, whereas the base addition salts are formedfrom acidic invention compounds. All of these forms are within the scopeof the compounds useful in the invention.

Pharmaceutically acceptable acid addition salts of the basic inventioncompounds include nontoxic salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,hydrofluoric, phosphorous, and the like, as well nontoxic salts derivedfrom organic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,malate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M. et al., “PharmaceuticalSalts,” J. of Pharma. Sci., 1977; 66:1).

An acid addition salt of a basic invention compound is prepared bycontacting the free base form of the compound with a sufficient amountof a desired acid to produce a nontoxic salt in the conventional manner.The free base form of the compound may be regenerated by contacting theacid addition salt so formed with a base, and isolating the free baseform of the compound in the conventional manner. The free base forms ofcompounds prepared according to a process of the present inventiondiffer from their respective acid addition salt forms somewhat incertain physical properties such as solubility, crystal structure,hygroscopicity, and the like, but otherwise free base forms of theinvention compounds and their respective acid addition salt forms areequivalent for purposes of the present invention.

A nontoxic pharmaceutically acceptable base addition salt of an acidicinvention compound may be prepared by contacting the free acid form ofthe compound with a metal cation such as an alkali or alkaline earthmetal cation, or an amine, especially an organic amine. Examples ofsuitable metal cations include sodium cation (Na⁺), potassium cation(K⁺), magnesium cation (Mg²⁺), calcium cation (Ca²⁺), and the like.Examples of suitable amines are N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, dicyclohexylamine,ethylenediamine, N-methylglucamine, and procaine (see, for example,Berge, supra., 1977).

A base addition salt of an acidic invention compound may be prepared bycontacting the free acid form of the compound with a sufficient amountof a desired base to produce the salt in the conventional manner. Thefree acid form of the compound may be regenerated by contacting the saltform so formed with an acid, and isolating the free acid of the compoundin the conventional manner. The free acid forms of the inventioncompounds differ from their respective salt forms somewhat in certainphysical properties such as solubility, crystal structure,hygroscopicity, and the like, but otherwise the salts are equivalent totheir respective free acid for purposes of the present invention.

Certain invention compounds can exist in unsolvated forms as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms, are equivalent to unsolvated forms andare encompassed within the scope of the present invention.

Certain of the invention compounds possess one or more chiral centers,and each center may exist in the R or S configuration. An inventioncompound includes any diastereomeric, enantiomeric, or epimeric form ofthe compound, as well as mixtures thereof.

Additionally, certain invention compounds may exist as geometric isomerssuch as the entgegen (E) and zusammen (Z) isomers of 1,2-disubstitutedalkenyl groups or cis and trans isomers of disubstituted cyclic groups.An invention compound includes any cis, trans, syn, anti, entgegen (E),or zusammen (Z) isomer of the compound, as well as mixtures thereof.

Certain invention compounds can exist as two or more tautomeric forms.Tautomeric forms of the invention compounds may interchange, forexample, via enolization/de-enolization, 1,2-hydride, 1,3-hydride, or1,4-hydride shifts, and the like. An invention compound includes anytautomeric form of the compound, as well as mixtures thereof.

Some compounds of the present invention have alkenyl groups, which mayexist as entgegen or zusammen conformations, in which case all geometricforms thereof, both entgegen and zusammen, cis and trans, and mixturesthereof, are within the scope of the present invention.

Some compounds of the present invention have cycloalkyl groups, whichmay be substituted at more than one carbon atom, in which case allgeometric forms thereof, both cis and trans, and mixtures thereof, arewithin the scope of the present invention.

The invention compounds also include isotopically-labelled compounds,which are identical to those recited above, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,^(˜)O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Compounds of thepresent invention and pharmaceutically acceptable salts of saidcompounds which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., 3H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of those described above in thisinvention can generally be prepared by carrying out the proceduresincorporated by reference above or disclosed in the Schemes and/or inthe Examples and Preparations below, by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

All of the above-describe forms of an invention compound are included bythe phrase “invention compound”, a “compound of Formula I”, a “compoundof Formula I, or a pharmaceutically acceptable salt thereof”, or anynamed species thereof, unless specifically excluded therefrom.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicillamine, auranofin or parenteral or oralgold.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as etoricoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

This invention also relates to a method of or a pharmaceuticalcomposition for treating inflammatory processes and diseases comprisingadministering a compound of this invention to a mammal, including ahuman, cat, livestock or dog, wherein said inflammatory processes anddiseases are defined as above and said inhibitory compound is used incombination with one or more other therapeutically active agents underthe following conditions:

A.) where a joint has become seriously inflamed as well as infected atthe same time by bacteria, fungi, protozoa and/or virus, said inhibitorycompound is administered in combination with one or more antibiotic,antifungal, antiprotozoal and/or antiviral therapeutic agents;

B.) where a multi-fold treatment of pain and inflammation is desired,said inhibitory compound is administered in combination with inhibitorsof other mediators of inflammation, comprising one or more membersindependently selected from the group consisting essentially of:

(1) NSAIDs;

(2) H₁-receptor antagonists;

(3) kinin-B₁- and B₂-receptor antagonists;

(4) prostaglandin inhibitors selected from the group consisting of PGD-,PGF—PGI₂- and PGE-receptor antagonists;

(5) thromboxane A₂ (TXA₂-) inhibitors;

(6) 5-, 12- and 15-lipoxygenase inhibitors;

(7) leukotriene LTC₄—, LTD₄/LTE₄- and LTB₄-inhibitors;

(8) PAF-receptor antagonists;

(9) gold in the form of an aurothio group together with one or morehydrophilic groups;

(10) immunosuppressive agents selected from the group consisting ofcyclosporine, azathioprine and methotrexate;

(11) anti-inflammatory glucocorticoids;

(12) penicillamine;

(13) hydroxychloroquine;

(14) anti-gout agents including colchicine; xanthine oxidase inhibitorsincluding allopurinol; and uricosuric agents selected from probenecid,sulfinpyrazone and benzbromarone;

C. where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

(1) cognitive therapeutics to counteract memory loss and impairment;

(2) anti-hypertensives and other cardiovascular drugs intended to offsetthe consequences of atherosclerosis, hypertension, myocardial ischemia,angina, congestive heart failure and myocardial infarction, selectedfrom the group consisting of:

a. diuretics;

b. vasodilators;

c. β-adrenergic receptor antagonists;

d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), aloneor optionally together with neutral endopeptidase inhibitors;

e. angiotensin II receptor antagonists;

f. renin inhibitors;

g. calcium channel blockers;

h. sympatholytic agents;

i. α₂-adrenergic agonists;

j. αadrenergic receptor antagonists; and

k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);

(3) antineoplastic agents selected from:

a. antimitotic drugs selected from:

i. vinca alkaloids selected from:

[1] vinblastine and

[2] vincristine;

(4) growth hormone secretagogues;

(5) strong analgesics;

(6) local and systemic anesthetics; and

(7) H₂-receptor antagonists, proton pump inhibitors and othergastroprotective agents.

The active ingredient of the present invention may be administered incombination with inhibitors of other mediators of inflammation,comprising one or more members selected from the group consistingessentially of the classes of such inhibitors and examples thereof whichinclude, matrix metalloproteinase inhibitors, aggrecanase inhibitors,TACE inhibitors, leucotriene receptor antagonists, IL-1 processing andrelease inhibitors, ILra, H₁-receptor antagonists; kinin-B₁- andB₂-receptor antagonists; prostaglandin inhibitors such as PGD-,PGF—PGI₂- and PGE-receptor antagonists; thromboxane A₂ (TXA2-)inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC₄—,LTD₄/LTE₄- and LTB₄-inhibitors; PAF-receptor antagonists; gold in theform of an aurothio group together with various hydrophilic groups;immunosuppressive agents, e.g., cyclosporine, azathioprine andmethotrexate; anti-inflammatory glucocorticoids; penicillamine;hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidaseinhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid,sulfinpyrazone and benzbromarone.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and alkaloids, such as vincristine and antimetabolites such asmethotrexate.

The compounds of the present invention may also be used in combinationwith anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, including hypertension,myocardial ischemia including angina, congestive heart failure andmyocardial infarction, selected from vasodilators such as hydralazine,β-adrenergic receptor antagonists such as propranolol, calcium channelblockers such as nifedipine, α₂-adrenergic agonists such as clonidine,α-adrenergic receptor antagonists such as prazosin and HMG-CoA-reductaseinhibitors (anti-hypercholesterolemics) such as lovastatin oratorvastatin.

The compounds of the present invention may also be administered incombination with one or more antibiotic, antifungal, antiprotozoal,antiviral or similar therapeutic agents.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metrifonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, lasofoxifene, droloxifeneor fosomax and immunosuppressant agents such as FK-506 and rapamycin.

The invention compounds may be used in combination with a COX-2selective inhibitor, more preferably celecoxib (e.g., CELEBREX®),valdecoxib (e.g., BEXTRA®), parecoxib, lumiracoxib (e.g., PREXIGE®), orrofecoxib (e.g., VIOXX®), or with compounds such as etanercept (e.g.,ENBREL®), infliximab (e.g., REMICADE®), leflunomide, (e.g., ARAVA®) ormethotrexate, and the like.

The invention compounds may be used in combination with biologicaltherapeutics useful for treating arthritic conditions, including CP-870,etanercept (a tumor necrosis factor alpha (“TNF-alpha”) receptorimmunoglobulin molecule; trade names ENBREL® and ENBREL ENTANERCEPT® byImmunex Corporation, Seattle, Wash.), infliximab (an anti-TNF-alphachimeric IgG 1K monoclonal antibody; tradename REMICADE® by Centocor,Inc., Malvern, Pa.), methotrexate (tradename RHEUMATREX® by AmericanCyanamid Company, Wayne, N.J.), and adalimumab (a human monoclonalanti-TNF-alpha antibody; tradename HUMIRA® by Abbott Laboratories,Abbott Park, Ill.).

The present invention also relates to the formulation of a compound ofthe present invention alone or with one or more other therapeutic agentswhich are to form the intended combination, including wherein saiddifferent drugs have varying half-lives, by creating controlled-releaseforms of said drugs with different release times which achievesrelatively uniform dosing; or, in the case of non-human patients, amedicated feed dosage form in which said drugs used in the combinationare present together in admixture in the feed composition. There isfurther provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the patient beingtreated, even though the individual drugs making up said combination arenot being administered to said patient simultaneously.

The invention method is useful in human and veterinary medicines fortreating mammals suffering from one or more of the above-listed diseasesand disorders.

All that is required to practice a method of this invention is toadminister a compound of Formula I, or a pharmaceutically acceptablesalt thereof, in an amount that is therapeutically effective forpreventing, inhibiting, or reversing the condition being treated. Theinvention compound can be administered directly or in a pharmaceuticalcomposition as described below.

A therapeutically effective amount, or, simply, effective amount, of aninvention compound will generally be from about 1 to about 300 mg/kg ofsubject body weight of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof. Typical doses will be from about 10 to about5000 mg/day for an adult subject of normal weight for each component ofthe combination. In a clinical setting, regulatory agencies such as, forexample, the Food and Drug Administration (“FDA”) in the U.S. mayrequire a particular therapeutically effective amount.

In determining what constitutes a nontoxic effective amount or atherapeutically effective amount of an invention compound for treating,preventing, or reversing one or more symptoms of any one of the diseasesand disorders described above that are being treated according to theinvention methods, a number of factors will generally be considered bythe medical practitioner or veterinarian in view of the experience ofthe medical practitioner or veterinarian, including the Food and DrugAdministration guidelines, or guidelines from an equivalent agency,published clinical studies, the subject's (e.g., mammal's) age, sex,weight and general condition, as well as the type and extent of thedisease, disorder or condition being treated, and the use of othermedications, if any, by the subject. As such, the administered dose mayfall within the ranges or concentrations recited above, or may varyoutside them, ie, either below or above those ranges, depending upon therequirements of the individual subject, the severity of the conditionbeing treated, and the particular therapeutic formulation beingemployed. Determination of a proper dose for a particular situation iswithin the skill of the medical or veterinary arts. Generally, treatmentmay be initiated using smaller dosages of the invention compound thatare less than optimum for a particular subject. Thereafter, the dosagecan be increased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Pharmaceutical compositions, described briefly here and more fullybelow, of an invention combination may be produced by formulating theinvention combination in dosage unit form with a pharmaceutical carrier.Some examples of dosage unit forms are tablets, capsules, pills,powders, aqueous and nonaqueous oral solutions and suspensions, andparenteral solutions packaged in containers containing either one orsome larger number of dosage units and capable of being subdivided intoindividual doses. Alternatively, the invention compounds may beformulated separately.

Some examples of suitable pharmaceutical carriers, includingpharmaceutical diluents, are gelatin capsules; sugars such as lactoseand sucrose; starches such as corn starch and potato starch; cellulosederivatives such as sodium carboxymethyl cellulose, ethyl cellulose,methyl cellulose, and cellulose acetate phthalate; gelatin; talc;stearic acid; magnesium stearate; vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma;propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar;alginic acid; isotonic saline, and phosphate buffer solutions; as wellas other compatible substances normally used in pharmaceuticalformulations.

The compositions to be employed in the invention can also contain othercomponents such as coloring agents, flavoring agents, and/orpreservatives. These materials, if present, are usually used inrelatively small amounts. The compositions can, if desired, also containother therapeutic agents commonly employed to treat any of theabove-listed diseases and disorders.

The percentage of the active ingredients of a compound of Formula I, ora pharmaceutically acceptable salt thereof, in the foregoingcompositions can be varied within wide limits, but for practicalpurposes it is preferably present in a total concentration of at least10% in a solid composition and at least 2% in a primary liquidcomposition. The most satisfactory compositions are those in which amuch higher proportion of the active ingredients are present, forexample, up to about 95%.

Preferred routes of administration of an invention compound are oral orparenteral. However, another route of administration may be preferreddepending upon the condition being treated. For exampled, topicaladministration or administration by injection may be preferred fortreating conditions localized to the skin or a joint. Administration bytransdermal patch may be preferred where, for example, it is desirableto effect sustained dosing.

It should be appreciated that the different routes of administration mayrequire different dosages. For example, a useful intravenous (“IV”) doseis between 5 and 50 mg, and a useful oral dosage is between 20 and 800mg, of a compound of Formula I, or a pharmaceutically acceptable saltthereof. The dosage is within the dosing range used in treatment of theabove-listed diseases, or as would be determined by the needs of thepatient as described by the physician.

The invention compounds may be administered in any form. Preferably,administration is in unit dosage form. A unit dosage form of theinvention compound to be used in this invention may also comprise othercompounds useful in the therapy of diseases described above. A furtherdescription of pharmaceutical formulations useful for administering theinvention compounds and invention combinations is provided below.

The active components of the invention combinations, may be formulatedtogether or separately and may be administered together or separately.The particular formulation and administration regimens used may betailored to the particular patient and condition being treated by apractitioner of ordinary skill in the medical or pharmaceutical arts.

The advantages of using an invention compound in a method of the instantinvention include the nontoxic nature of the compounds at andsubstantially above therapeutically effective doses, their ease ofpreparation, the fact that the compounds are well-tolerated, and theease of topical, IV, or oral administration of the drugs.

Another important advantage is that the present invention compounds moreeffectively target a particular disease that is responsive to inhibitionof MMP-13 with fewer undesirable side effects than similar compoundsthat inhibit MMP-13 that are not invention compounds. This is so becausethe instant invention compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, do not directly, or indirectly via a bridgingwater molecule, ligate, coordinate to, or bind to the catalytic zinccation of MMP-13, but instead bind at a different location from wherenatural substrate binds to MMP-13. The binding requirements of anallosteric MMP-13 binding site are unique to MMP-13, and account for thespecificity of the invention compounds for inhibiting MMP-13 over anyother MMP enzyme. This binding mode has not been reported in the art.Indeed, prior art inhibitors of MMP-13 bind to the catalytic zinccations of other MMP enzymes as well as to the catalytic zinc cation ofMMP-13, and are consequently significantly less selective inhibitors ofMMP-13 enzyme.

The invention compounds which are invention compounds, andpharmaceutically acceptable salts thereof, are thus therapeuticallysuperior to other inhibitors of MMP-13, or even tumor necrosisfactor-alpha converting enzyme (“TACE”), because of fewer undesirableside effects from inhibition of the other MMP enzymes or TACE. Forexample, virtually all prior art MMP inhibitors tested clinically todate have exhibited an undesirable side effect known as muscoloskeletalsyndrome (“MSS”). MSS is associated with administering an inhibitor ofmultiple MMP enzymes or an inhibitor of a particular MMP enzyme such asMMP-1. MSS will be significantly reduced in type and severity byadministering the invention compound instead of any prior art MMP-13inhibitor, or a pharmaceutically acceptable salt thereof. The inventioncompounds are superior to similar compounds that interact with thecatalytic zinc cation of the MMP-13 enzyme as discussed above, even ifsimilar compounds show some selectivity for the MMP-13.

It is expected that nearly all, if not all, compounds of Formula I, orpharmaceutically acceptable salts thereof, are invention compounds.

This advantage of the instant compounds will also significantly increasethe likelihood that agencies which regulate new drug approvals, such asthe United States Food and Drug Administration, will approve the instantcompounds versus a competing similar compound that does notallosterically bind to MMP-13 as discussed above even in the unlikelyevent that the two compounds behaved similarly in clinical trials. Theseregulatory agencies are increasingly aware that clinical trials, whichtest drug in limited population groups, do not always uncover safetyproblems with a drug, and thus all other things being equal, theagencies will favor the drug with the lowest odds of producingundesirable side effects.

Another important advantage is that the disease modifying properties ofthe invention compounds provide patients suffering from cartilagedamage, arthritis, preferably osteoarthritis, inflammation and/or painwith both relief of symptoms and prevention or inhibition of theunderlying disease pathology such as cartilage degradation. There is nocurrently approved drug for disease modification of cartilage damage,including in osteoarthritis.

Any invention compound is readily available, either commercially, or bysynthetic methodology, well known to those skilled in the art of organicchemistry. For specific syntheses, see the examples below and thepreparations of invention compound outlined in the Schemes below.

Intermediates for the synthesis of a compound of Formula I, or apharmaceutically acceptable salt thereof, may be prepared by one ofordinary skill in the art of organic chemistry by adapting varioussynthetic procedures incorporated by reference above or that arewell-known in the art of organic chemistry. These synthetic proceduresmay be found in the literature in, for example, Reagents for OrganicSynthesis, by Fieser and Fieser, John Wiley & Sons, Inc, New York, 2000;Comprehensive Organic Transformations, by Richard C. Larock, VCHPublishers, Inc, New York, 1989; the series Compendium of OrganicSynthetic Methods, 1989, by Wiley-Interscience; the text AdvancedOrganic Chemistry, 4^(th) edition, by Jerry March, Wiley-Interscience,New York, 1992; or the Handbook of Heterocyclic Chemistry by Alan R.Katritzky, Pergamon Press Ltd, London, 1985, to name a few.Alternatively, a skilled artisan may find methods useful for preparingthe intermediates in the chemical literature by searching widelyavailable databases such as, for example, those available from theChemical Abstracts Service, Columbus, Ohio, or MDL Information SystemsGmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany.

Preparations of the invention compounds may use starting materials,reagents, solvents, and catalysts that may be purchased from commercialsources or they may be readily prepared by adapting procedures in thereferences or resources cited above. Commercial sources of startingmaterials, reagents, solvents, and catalysts useful in preparinginvention compounds include, for example, The Aldrich Chemical Company,and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo.,BACHEM, BACHEM A. G., Switzerland, or Lancaster Synthesis Ltd, UnitedKingdom.

Syntheses of some invention compounds may utilize starting materials,intermediates, or reaction products that contain a reactive functionalgroup. During chemical reactions, a reactive functional group may beprotected from reacting by a protecting group that renders the reactivefunctional group substantially inert to the reaction conditionsemployed. A protecting group is introduced onto a starting materialprior to carrying out the reaction step for which a protecting group isneeded. Once the protecting group is no longer needed, the protectinggroup can be removed. It is well within the ordinary skill in the art tointroduce protecting groups during a synthesis of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, and then later removethem. Procedures for introducing and removing protecting groups areknown and referenced such as, for example, in Protective Groups inOrganic Synthesis, 2^(nd) ed., Greene T. W. and Wuts P. G., John Wiley &Sons, New York: N.Y., 1991, which is hereby incorporated by reference.

Thus, for example, protecting groups such as the following may beutilized to protect amino, hydroxyl, and other groups: carboxylic acylgroups such as, for example, formyl, acetyl, and trifluoroacetyl;alkoxycarbonyl groups such as, for example, ethoxycarbonyl,tert-butoxycarbonyl (BOC), β,β,β-trichloroethoxycarbonyl (TCEC), andβ-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example,benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl, and9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, forexample, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); andother groups such as, for example, triphenylmethyl (trityl),tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl,diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl,trifluoromethanesulfonyl, and benzyl. Examples of procedures for removalof protecting groups include hydrogenolysis of CBZ groups using, forexample, hydrogen gas at 50 psi in the presence of a hydrogenationcatalyst such as 10% palladium on carbon, acidolysis of BOC groupsusing, for example, hydrogen chloride in dichloromethane,trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction ofsilyl groups with fluoride ions, and reductive cleavage of TCEC groupswith zinc metal.

Compounds of Formula I may be prepared according to the synthetic routeoutlined in Scheme 1. In Scheme 1, commercially available 3-cyanobenzoicacid 1 undergoes a 3+2 cycloaddition reaction with azides selected fromsodium azide, tributyltin azide, or trimethylsilyl azide in a suitablesolvent such as toluene or p-dioxane and in the presence oftriethylamine hydrochloride or ammonium chloride to form thecorresponding tetrazole derivative. The carboxylic acid functionality isreacted with HCl in methanol at room temperature or under refluxconditions to give the ester intermediate 2. Compound 2 in Scheme 1 isallowed to react with a variety of alkyl halides or mesylates ofcommercially available alcohols in the presence of a base such astriethylamine, cesium carbonate, or sodium carbonate in a suitablesolvent such as acetonitrile or dimethylformamide.

The resulting 1- and 2-substituted regioisomers are separatedanalytically pure using purification methods known in the art such assilica gel chromatography or recrystallization from solvents such ashexane/ethyl acetate or petroleum ether/diethyl ether. The esterfunctionality of intermediate 3 is converted to the corresponding acid 5in the presence of a base such as sodium or lithium hydroxide in aprotic solvent such as ethanol, methanol, or water. Acidification of thecarboxylate salt using an acid such as hydrochloric acid, acetic acid,or trifluoroacetic acid yields the acid intermediate 5. The acid isconverted to the acid chloride with oxalyl chloride or allowed to reactwith a coupling agent such as DCC or EDC in the presence of HOBT in asuitable solvent such as dichloromethane, tetrahydrofuran, ordimethylformamide. These reactive intermediates are coupled with avariety of primary and secondary amine nucleophiles includingbenzylamine, isopropylamine, and 3-picolylmethylamine to name a few.

Compounds of Formula I wherein S, T, or U are C—OCH3 are prepared asshown in Scheme 2. The 3-bromo-4-methoxybenzonitrile 7 is converted tothe tetrazole and alkylated to compounds 9 and 10 using reactionconditions described for intermediates 2,3, and 4 in Scheme 1.Intermediate 9 is carbonylated in the presence of a suitable couplingreagent such as a palladium catalyst, includingbis(triphenylphosphinyl)chloride, palladium acetate, or palladiumtetrakis triphenylphosphine, in the presence of a base such as atertiary organic amine, including triethylamine ordiisopropylethylamine, in a protic solvent such as methanol and under anatmosphere of carbon monoxide whose pressure and temperature may requireas high as 500 psi and 100° C. Compound 11 can then be converted to avariety of amides 13 utilizing the experimental conditions previouslydescribed in Scheme 1.

Compound 7 in Scheme 2 can be replaced with commercially availablepyridine based nitrites 14 as shown in Scheme 3. These compounds areconverted to the corresponding tetrazole amides 20 utilizing thereaction conditions described in Scheme 2 for compound 14.

Alternatively in Scheme 4, the acid chloride prepared in Scheme 1 can beconverted to the corresponding primary alcohol 22 in the presence of asuitable reducing agent such as lithium aluminum hydride or sodiumborohydride in an aprotic solvent such a dichloromethane ortetrahydrofuran at temperatures ranging between 0° C. and 60° C. Thealcohol 22 is converted to the corresponding bromide 23 usingphosphorous tribromide in a halogenated solvent includingdichloromethane, carbon tetrachloride, or chloroform. Intermediate 23can be coupled with a variety of primary and secondary amines in thepresence of a tertiary amine including diisopropylethylamine ortriethylamine in suitable solvent such as dichloromethane ortetrahydrofuran at temperatures ranging from as low as room temperatureto as high as reflux to give tetrazole amine 24. Coupling alkyl halide23 with a variety of alcohols including benzyl alcohol or phenol and inthe presence of a base such as sodium hydride or cesium carbonate in anappropriate solvent such as dimethylformamide or tetrahydrofuran yieldsthe corresponding tetrazole ether derivative 25.

The synthesis of alkyne derivatives is presented in Scheme 5. The iodosubstituted intermediate 28 is coupled with an appropriately substitutedalkyne such as 3-phenyl-1-propyne or (1,1-difluoro-prop-2-ynyl)-benzenein the presence of copper(I) iodide and a tertiary organic baseincluding diisopropylethylamine or triethylamine. The reaction iscatalyzed by a palladium catalyst such as tetrakis (triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) dichloride to yieldthe corresponding alkyne derivatives 30.

The synthesis of compounds of Formula I wherein V is a 5-memberedheteroaryleneyl such as an oxazolenyl or thiazolenyl is illustratedbelow in Scheme 6. In Scheme 6,3-iodo-benzoic acid (1) is allowed toreact with an alpha-amino ketone hydrochloride of formula (2) (prepared,for example, by allowing ammonia to react with an alpha-(Cl, Br, orI)-4-carboxymethyl-acetophenone in a solvent such as tetrahydrofuran(“THF”) at a temperature of from about −33 to room temperature) to givethe keto-amide compound of formula (3). The compound of formula (3) iscyclized under acidic dehydrating conditions such as with an acidcatalyst selected from polyphosphoric acid, para-toluenesulfonic acid,amberlyst-15 resin, methanesulfonic acid, trifluoroacetic acid,trifluoromethanesulfonic acid, titanium tetrachloride, and the like inthe presence of a suitable dehydrating reagent selected from aDean-Stark trap, activated 3-angstrom molecular sieves, anhydrousmagnesium sulfate, phosphorous pentoxide, and the like in a suitablesolvent such as toluene, dichloromethane (“DCM”), THF, xylenes, and thelike at a suitable temperature such as from about 0° C. to about 200° C.to give the oxazole-ester of formula (4). The oxazole-ester of formula(4) is saponified to give the corresponding oxazole-acid, which is thencoupled with a 3-substituted propylene of formula (5) using conditionsdescribed above in previous examples or palladium, copper(I) iodide, andHünig's base or 1,8-diazabicyclo[5.4.0]undec-7-ene to give an oxazolecompound of formula (6).

Alternatively in Scheme 6, the keto-amide compound of formula (3) issulfurated with, for example, P₂S₅, to give the correspondingketo-thioamide, which is cyclized as previously described forcyclization of the keto-amide of formula (3) to give the thiazole-esterof formula (7). The thiazole-ester of formula (7) is then converted inseveral steps to the thiazole compound of the present invention offormula (8) according to the methods described above for conversion ofthe oxazole-ester of formula (4) to the compound of formula (6).

Another synthesis of compounds of Formula I wherein V is a 5-memberedheteroaryleneyl such as a oxadiazolenyl or thiadiazolenyl is illustratedbelow in Scheme 7. In Scheme 7,3-iodo-benzoic acid (1) is coupled withN-tertbutyloxycarbonyl-hydrazine (“N—BOC-hydrazine”) in the presence ofa suitable coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDC,”“EDCI,” or “EDAC”), N,N′-carbonyldiimidazole (“CDI”) orN,N′-dicyclohexylcarbodiimide (“DCC”) with 1-hydroxybenzotriazole(“HOBt”) in a suitable solvent such as THF, DCM, and the like at asuitable temperature such as from about −30° C. to about 100° C.,followed by acid catalyzed cleavage of the BOC group (e.g., HCl gas inDCM or ethyl acetate) to give an acyl-hydrazine, which is then coupledin a similar fashion with 4-carbomethoxybenzoic acid (2) to give thebisacyl-hydrazine-ester of formula (3). Following procedures analogousto those described above for Scheme 6, the bisacyl-hydrazine-ester offormula (3) is then cyclized under acid dehydrating conditions to givethe oxadiaole-ester of formula (4), which is saponified, and theresulting oxadiazole-acid coupled with a 3-substituted propyne offormula (5) to give an oxadiazole compound of formula (6).

Alternatively, following procedures analogous to those described abovefor Scheme 6, the bisacyl-hydrazine-ester of formula (3) is sulfuratedwith P₂S₅ or the like, and cyclized under acid dehydrating conditions togive the oxadiaole-ester of formula (7), which is saponified, and theresulting oxadiazole-acid coupled with a 3-substituted propyne offormula (5) to give a thiadiazole compound of formula (8).

The synthesis of compounds of Formula I wherein Q is

such as an oxazolenyl or thiazolenyl is illustrated below in Schemes8-10. In Scheme 8,3-cyano-benzoic acid (1) is allowed to react with analpha-amino ketone hydrochloride of formula (2) (prepared, for example,by allowing ammonia to react with an alpha-(Cl, Br, orI)-4-methoxy-acetophenone in a solvent such as tetrahydrofuran (“THF”)at a temperature of from about −33 to room temperature) to give theketo-amide compound of formula (3). The compound of formula (3) iscondensed with sodium azide under conventional tetrazole-ring formingconditions such as in the presence of a weak acid such as triethylaminehydrochloride in a suitable solvent such as THF and the like attemperatures from about 0° C. to about 120° C. to give thetetrazole-keto-amide of formula (4). Tri-(n-butyl)tin azide may be usedalso to synthesize the tetrazole-keto-amide of formula (4). Followingthe procedures described above for Scheme 6, the keto-amide of formula(4) is then cyclized under acid dehydrating conditions to give theoxazole-tetrazole of formula (5). The oxazole-tetrazole of formula (5)is alkylated with a suitable alkylating agent such as the bromo-ester offormula (6), and the resulting oxazole-tetrazole-ester is hydrolyzedunder acidic conditions to give an oxazole-acid compound of formula (7).

Alternatively, following procedures analogous to those described abovefor Scheme 6, the keto-amide of formula (4) is sulfurated with P₂S₅ orthe like, and cyclized under acid dehydrating conditions to give thethiazole-tetrazole of formula (8). The thiazole-tetrazole of formula (8)is then alkylated with a suitable alkylating agent such as thebromo-ester of formula (6), and the resulting thiazole-tetrazole-esteris hydrolyzed under acidic conditions to give a thiazole-acid compoundof formula (9).

In Scheme 9, isophthalic acid monomethyl ester of formula (1) is coupledwith N—BOC-hydrazine and the BOC group is cleaved as described above forScheme 7 to give the ester-acylhydrazine hydrochloride of formula (2).The ester-acylhydrazine hydrochloride (2) is coupled with4-carboxymethylbenzoic acid methyl ester of formula (3) usingconventional conditions such as EDAC HCl, HOBt, N,N′-dimethylformamide(“DMF”), as described above to give the ester-bisacylhydrazine offormula (4). The ester-bisacylhydrazine of formula (4) is cyclized underacidic dehydrating conditions such as those described above for Scheme 7to give the ester-oxadiazole of formula (5). The ester-oxadiazole offormula (5) is then saponified to give the correspondingacid-oxadiazole, which is coupled with an alpha-amino ketonehydrochloride of formula (6) under conventional conditions as describedabove for Scheme 8 to give the keto-amide-oxadiazole-ester of formula(7). The keto-amide-oxadiazole-ester of formula (7) is cyclized underacidic dehydrating conditions as described above, and the estersaponified to give the oxazole-oxadiazole-ester of formula (8).

Alternatively, following the procedures described above for Scheme 7,the ester-bisacylhydrazine of formula (4) is sulfurated, and theintermediate is cyclized under acidic dehydrating conditions to give acompound of formula (9), which is converted to the compound of formula(10) as described above, which is converted to the compound of formula(11) as described above.

Alternatively, following the procedures described above for Scheme 6,the compound of formula (7) is sulfurated, and the intermediate iscyclized under acidic dehydrating conditions to give a compound offormula (12) as described above.

Alternatively, following the procedures described above for Schemes 6and 7, the compound of formula (10) is sulfurated, and the intermediateis cyclized under acidic dehydrating conditions to give a compound offormula (13) as described above.

Alternatively in Scheme 9a, compounds of formulas (5) or (9) may beconverted to compounds of formulas (17), (18), (19), and (20) bysubstituting the compound of Formula (14) in Scheme 9a for the compoundof formula (6) in Scheme 9, and converting the resulting compounds asdescribed for Scheme 9.

In Scheme 10, isophthalic acid monomethyl ester of formula (1) iscoupled with 4-methoxybenzylamine of formula (2) using conventionalconditions as described previously to give the keto-amide of formula(3). The ester-keto-amide of formula (3) is structurally related to theester-bisacylhydrazine of formula (4) in Scheme 9. In a manner similarto that illustrated above in Scheme 9 for the conversion of theester-bisacylhydrazine of formula (4) to the compounds of formulas (8),(11), (12), and (13), the compounds of formulas (4), (5), (6), and (7),respectively in Scheme 10 may be prepared.

Alternatively in Scheme 10, a compound of formula (3) may be convertedto compounds of formulas (8), (9), (10), and (11) by substituting4-methoxy-benzoylhydrazine hydrochloride for the alpha-amino ketonehydrochloride of formula (6) in Scheme 9, and converting the resultingcompounds as described for Scheme 9.

wherein R¹ and R³ are as defined above for Formula I and R^(2a)CH₂ is asubset of the group R² of Formula I.

wherein R¹ and R³ are as defined above for Formula I and R^(2a)CH₂ is asubset of the group R² of Formula I.

wherein R¹ and R³ are as defined above for Formula I and R^(2a)CH₂ is asubset of the group R² of Formula I.

wherein R¹ and R³ are as defined above for Formula I and R^(2a)CH₂ is asubset of the group R² of Formula I.

wherein R¹ and R³ are as defined above for Formula I and R^(2a)CH₂ is asubset of the group R² of Formula I.

It should be appreciated that when Q is trans-(H)C═C(H), cis-(H)C═C(H),C≡C, CH₂C≡C, or CF₂C≡C and is bonded to a sp² carbon atom in Formula I,a palladium catalyzed coupling of the corresponding terminal olefin oralkyne of formulas R¹-(trans-(H)C═CH₂), R¹-(cis-(H)C═CH₂), R¹—C≡CH,R¹—CH₂C≡CH, or R¹—CF₂C≡CH, wherein R¹ is as defined above, with a bromo-or iodo-substituted sp² carbon atom of formula:

in the presence of a suitable base will yield a compound of Formula Iwherein Q is trans-(H)C═C(H), cis-(H)C═C(H), C≡C, CH₂C≡C, or CF₂C≡C andD is a group that is bonded to Q at a sp² carbon atom, and R¹, V, and R²are as defined above for Formula I. Illustrative examples of thecoupling reagents and catalysts include palladiumtetrakis(triphenylphosphine) or palladium(II) acetate as catalyst, atertiary organic amine base such as triethylamine ordiisopropylethylamine, a suitable solvent such as dimethylformamide(“DMF”) or tetrahydrofuran (“THF”), and optionally a co-catalyst such ascopper(I) iodide, at a suitable temperature such as from 0° C. to 100°C., for a suitable time such as from 30 minutes to 2 days, and under aninert atmosphere such as an atmosphere of nitrogen or argon gas.

Alternatively, a corresponding aldehyde of formula

prepared as described below, may be coupled with a phosphonium ylideunder Wittig olefination, or Horner-Emmons olefination, conditions togive a compound of Formula I wherein Q is trans-(H)C═C(H).

The bromo or iodo intermediates described above may be converted byconventional means to the corresponding carboxylic acid of formula

and the carboxylic acid converted by conventional means to compounds ofFormula I wherein Q is OC(O), CH(R⁶)C(O), OC(NR⁶), CH(R⁶)C(NR⁶),N(R⁶)C(O), N(R⁶)C(S), N(R⁶)C(NR⁶), SC(O), CH(R⁶)C(S), or SC(NR⁶).Illustrative examples include coupling of the carboxylic acid with anamine to provide a compound of Formula I wherein Q is N(R⁶)C(O), andoptionally sulfurating the resulting amide with, for example P₂S₅ toprovide a compound of Formula I wherein Q is N(R⁶)C(S). Alternatively,the carboxylic acid may be coupled with an alcohol to provide a compoundof Formula I wherein Q is OC(O).

Alternatively, the carboxylic acid may be reduced to the correspondinghydroxymethyl compound of formula

and the hydroxymethyl converted to a compound of Formula I wherein Q isOCH₂ or N(R⁶)CH₂ by conventional means.

Alternatively, the hydroxymethyl compound may be oxidized to thecorresponding aldehyde of formula

and the aldehyde coupled with hydroxylamine to give a correspondingoxime. The oxime may be chlorinated, and the chlorooxime cyclized withan olefin or alkyne to give a compound of Formula I wherein Q is a5-membered heteroarylene.

Alternatively, the aldehyde may be prepared from the correspondingcarboxylic acid by coupling the carboxylic acid withN,O-dimethylhydroxylamine and reducing the resulting dimethylhydroxamidewith a suitable hydride reducing agent such as sodium borohydride orlithium aluminum hydride.

Alternatively, the above-described carboxylic acid intermediate may beconverted by conventional means to the corresponding methyl ketone offormula

and the methyl ketone may be halogenated on methyl and coupled withvarious amines, alcohols, or other halogenated compounds to give acompound of Formula I wherein Q is CH(R⁶)C(O).

Alternatively, the above-described carboxylic acid intermediate orbromo- or iodo-intermediates may be converted by conventional means tothe corresponding nitrile of formula

and the nitrile condensed with an amine or alcohol undernon-nucleophilic basic conditions (e.g., 1,8-diazaundecane) to give acompound of Formula I wherein Q is N(R⁶)C(NR⁶) or OC(NR⁶), respectively.

Alternatively, compounds of Formula I wherein Q is a lactam diradicalmay be prepared by conventional means by cyclizing the correspondinggamma-amino acids.

The synthesis of certain intermediates are described below in thePreparations.

Preparation 1 Synthesis of Isophthalic Acid Monomethyl Ester

The following were introduced into a vessel: 10.0 g (40.3 mmol) ofmethyl 3-bromobenzoate, 2.5 g (mmol) of1,3-bis(diphenylphosphino)propane (“DPPP”), 14 mL of triethylamine,0.905 g of palladium acetate, and 140 ml of methanol. The vessel wassealed and pressurized with carbon monoxide to a pressure of 500 psi.The vessel was heated to 100° C. for 15 hours. The mixture was thencooled and concentrated on a rotary evaporator before partitioningbetween EtOAc and 2M HCl. The layers were separated, and the aqueouslayer was extracted with EtOAc (1×). The organic extracts were combinedand washed with saturated aqueous NaCl solution and dried (MgSO₄).Concentration provided a solid, which is slurried in hexane andfiltered. The material is dried in a vacuum oven at ˜10 mmHg at 70° C.;yield 5.9 g (82%).

NMR: DMSO ¹H δ (ppm) 3.54 (3H, s); 7.18-7.21 (1H, m); 7.34-7.40 (1H, m);7.46-7.49 (1H m); 7.87-7.89 (1H, m).

Preparation 2 Synthesis ofN-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester

1.8 g (5.5 mmol) of isophthalic acid monomethyl ester from Preparation1, 3.5 g (18.5 mmol) of EDAC.HCl, 2.5 g (18.5 mmol) of HOBt, and 3.1 g(15.4 mmol) of 2-amino-1-(4-methoxy-phenyl)-ethanone hydrochloride weredissolved in 20 mL of dimethylformamide. 1.9 g (15.4 mmol) ofdi-isopropyl ethylamine was then added. Stirring was continued overnightat room temperature. Water (60 ml) was added, and the product wasfiltered, washed with water. The resulting solid was triturated in hotmethanol, filtered and dried in a vacuum oven overnight at 70° C. toprovide 3.5 g (69%) desired product. MS: m/z (APCI, AP+) 328 [M^(.)]⁺NMR: DMSO ¹H δ (ppm) 3.84 (3H, s); 3.88 (3H, s); 4.73 (2H, d, J=5.6 Hz);7.04-7.08 (2H m); 7.63-7.66 (1H, t, J=7.8 Hz); 7.99-8.027 (2H, m);8.097-8.16 (2H, m); 8.47-8.48 (1H, m); 9.00-9.03 (1H, t, J=5.8 Hz).

Preparation 3 Synthesis of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoicacid methyl ester

0.5 g 1.5 mmol) of N-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamicacid methylester from Preparation 2 was dissolved in ˜15 mL of polyphosphoric acid. The mixture was stirred at 80° C. for 2 hours beforeallowing it to cool to room temperature. Water (60 mL) was added, andthe product precipitated upon agitation. The solid was filtered andwashed with water. Slurried solid product in hot methanol and filtered.Dried in vacuum oven overnight to obtain 0.38 (80%) desired products

Preparation 4 Synthesis of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoicacid

A solution of 1.7 g (5.5 mmol)N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester fromPreparation 3 in a 3:1:1 mixture of THF/methanol/water was added 10 mL(10 mmol) 1N NaOH. The mixture was stirred 4 hours at room temperaturebefore concentrating on a rotary evaporator. The residue was treatedwith 6M HCl then filtered, washed with water (iX) and dried in a vacuumoven overnight at 70° C. to provide 1.5 g (91%) desired product.

MS: m/z (APCI, AP+) 296 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.79 (3H, s); 7.03-7.07 (2H, m); 7.65-7.79 (4H, m);8.03-8.06 (1H m); 8.26-8.28 (1H m); 8.54-8.55 (1H, m).

Preparation 5 Synthesis ofN′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazinecarboxylicacid tert-butyl ester

1.5 g (5.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acidfrom Preparation 4, 1.3 g (6.6 mmol) EDAC.HCl, 0.89 g (6.6 mmol) HOBT,and 0.87 g (6.6 mmol) hydrazinecarboxylic acid tert-butyl ester wasdissolved in 20 mL of dimethylformamide. Stirring was continued 48 hoursat room temperature. Water (60 mL) was added, and the product wasextracted with 1:1 THF/EtOAc (2×). Combined the organic extracts andwashed with saturated aqueous NaCl solution (3×), dried (MgSO₄). Driedin a vacuum oven overnight at 70° C. to provide 1.6 g (82%) of desiredproduct. MS: m/z (APCI, AP+) 410 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 1.48 (9H, s); 3.84 (3H, m); 6.93-6.96 (2H, m);7.25-7.29 (2H m); 7.36-7.53 (2H, m); 7.60-7.63 (1H, m); 7.69-7.92; 8.00(1H, s); 8.16-8.48 (1H, m).

Preparation 6 Synthesis of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoicacid hydrazide

To a 0° C. suspension of 2.0 g (5.0 mmol)N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazinecarboxylicacid tert-butyl ester from Preparation 5 in 30 mL EtOAC was bubbled HClgas for 3 minutes. Gas flow was stopped and the mixture was stirred 2hours. The solid product was filtered off and washed with EtOAc. Driedin a vacuum oven at 70° C. overnight to obtain 1.5 g (96%) desired whitesolid. MS: m/z (APCI, AP+) [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) (9H, s); (3H, m); (2H, m); (2H m); (2H, m); (1H,m); 8 (1H, s).

Preparation 7 Synthesis of 4-Carboxymethyl-benzoic acid methyl ester

30.0 g (139 mmol) of (4-Bromo-phenyl)-acetic acid 5.7 g (14 mmol) DPPP,32.4 mL of triethylamine, 2.08 g palladium acetate and 300 mL ofmethanol were introduced into a vessel. The vessel was sealed andpressurized with carbon monoxide to a pressure of 500 psi. The vesselwas heated at 100° C. for 15 hours. The mixture was then cooled andconcentrated on a rotary evaporator before partitioning between EtOAcand 2M HCl. Separated and extracted the aqueous layer with EtOAc (1×).The organic extracts were combined and washed with saturated aqueousNaCl solution and dried (MgSO4). Concentration provided a solid whichwas slurried in hexane and filtered. The material was dried in a vacuumoven at ˜10 mmHg at 70° C.; yield 24 g (88%)

MS: m/z (APCI, AP⁻) 179 [M^(.)]⁻

NMR: DMSO ¹H δ (ppm) 3.86 (3H, s); 7.63-7.67 (1H, m); 8.15-8.18 (2H, m);8.45-8.46 (1H m).

Preparation 8 Synthesis of4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoicacid methyl ester

0.7 g (2.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acidhydrazide hydrochloride from Preparation 6, 0.49 g (2.6 mmol) EDAC.HCl,0.35 g (2.6 mmol) HOBT, and 0.50 g (2.6 mmol) 4-carboxymethyl-benzoicacid methyl ester from Preparation 7 was dissolved in 20 mL ofdimethylformamide. 0.33 g (2.6 mmol) Di-isopropylethylamine was thenadded. Stirring was continued 14 hours at room temperature. Water (60ml) was added and the product was extracted with 1:1 Et₂O/EtOAc (2×).Combined the organic extracts and washed with saturated aqueous NaClsolution (4×), dried (MgSO₄). The resulting solid was triturated inEtOAc and filtered. Dried in a vacuum oven overnight at 70° C. toprovide 0.48 g (49%) desired product. MS: m/z (APCI, AP+) 486 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.66 (2H, s); 3.79 (3H, s); 3.83 (3H, s); 7.04-7.08(2H, m); 7.48-7.50 (2H, m); 7.53-7.98 (9H, m); 7.99-8.24 (1H, m);8.52-8.53 (1H, m).

Preparation 9 Synthesis of4-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazinocarbonyl)-benzoicacid methyl ester

Using the procedure from Preparation 8 and terephthalic acid monomethylester in place of 4-carboxymethyl-benzoic acid methyl ester fromPreparation 7 was obtained 0.48 g (50%) of desired white solid. MS: m/z(APCI, AP+) 472 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.77 (3H, s); 3.85 (3H, s); 7.03-7.05 (2H, d);7.66-7.78 (4H, m); 8.00-8.07 (5H, m); 8.23-8.25 (1H, d); 8.56 (1H, s);10.77-10.81 (2H, broad m).

Preparation 10 Synthesis of3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid methyl ester

To a suspension of 1.4 g (4.3 mmol)N-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester fromPreparation 2 in 30 mL of dry dioxane was added 1.1 g (5.2 mmol) of P₂S₅in one portion. The resulting mixture was warmed to 50° C. for 1 hourbefore cooling to room temperature and adding about 60 ml water. Stirred2 hours and then filtered off solid product. Triturated in hot MeOH andfiltered. Dissolved in THF and filtered through a plug of flash silicagel with THF eluent. Concentration gave 1.4 g (100%) of desired product.Used directly in the procedure of Preparation 11 withoutcharacterization.

Preparation 11 Synthesis of3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid

A solution of 1.4 g (4.3 mmol)3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid methyl ester fromPreparation 10 in a 3:1:1 mixture of THF/methanol/water was added 10 mL(10 mmol) 1N NaOH. The mixture was stirred 14 hours at room temperaturebefore concentrating on a rotary evaporator. The residue was treatedwith 6M HCl then filtered, washed with water (1×) and dried in a vacuumoven overnight at 70° C. to provide 1.2 g (88%) of desired product.

MS: m/z (APCI, AP+) 312 [M^(.)]⁺ NMR: DMSO ¹H δ (ppm) 3.79 (3H, s);7.00-7.07 (2H, m); 7.61-7.67 (3H, m); 7.99-8.02 (1H, m); 8.14-8.17 (1H,m); 8.22-(1H, s); 8.44-8.45 (1H, m).

Preparation 12 Synthesis ofN′-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoyl}-hydrazinecarboxylicacid tert-butyl ester

Using the procedure from Example B2 and 1.2 g (3.8 mmol)3-[5-(4-methoxy-phenyl)-thiazol-2-yl]-benzoic acid from Preparation 11as starting material, the desired product was obtained.

Preparation 13 Synthesis of3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid hydrazidehydrochloride

Using the procedure from Preparation 6 and 0.85 g (2.0 mmol)N′-{3-[5-(4-methoxy-phenyl)-thiazol-2-yl]-benzoyl}-hydrazinecarboxylicacid tert-butyl ester from Preparation 12, 0.68 g (45%) desired productwas obtained.

MS: m/z (APCI, AP+) 326 [M^(.)]⁺ NMR: DMSO ¹H δ (ppm) 3.79 (3H, s);7.01-7.05 (2H, m); 7.64-7.74 (3H, m); 8.00-8.01 (1H, m); 8.03-8.18 (1H,m); 8.24-(1H, s); 8.45-8.46 (1H, m).

Preparation 14 Synthesis of4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoicacid methyl ester

Using the procedure from Preparation 8 and 0.67 (2.1 mmol)3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid hydrazidehydrochloride from Preparation 13 0.35 (33%) of desired product wasobtained. MS: m/z (APCI, AP+) 502 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.65 (2H, s); 3.79 (3H, s); 3.83 (3H, s); 7.00-7.04(2H, m); 7.48-7.67 (5H, m); 7.90-7.95 (3H, m); 8.11-8.13 (1H, m); 8.24(1H, s); 8.40-8.41 (1H, m).

Illustrative examples of the synthesis of compounds of Formula I aredescribed below in the Examples.

EXAMPLE 1 Step (a): 3-(2H-Tetrazol-5-yl)benzoic acid methyl ester

To a solution of 3-cyanobenzoic acid (12.3 g, 0.083 mol) in toluene (300mL) were added sodium azide (16 g, 0.25 mol) and triethylaminehydrochloride (34 g, 0.25 mol) respectively. The reaction mixture wasrefluxed for 4 hours, cooled to room temperature, and diluted with water(300 mL). The organic phase was separated and the aqueous portion wasacidified (pH=1) using concentrated HCl. The precipitate was collectedby filtration and oven-dried to give 14 g (89%) of the tetrazole as awhite solid. CI-MS: C8H6N4O2 [M+1] 191.0. The product obtained (14 g,0.074 mol) was suspended in anhydrous methanol followed by the additionof gaseous HCl over a period of 20 minutes. The warm solution wasstirred at room temperature for overnight, then concentrated in vacuo.The resulting residue was triturated with diethyl ether and collected byfiltration to yield 12.1 g (81%) of the methyl ester intermediate 2.CI-MS: C9H8N4O2 [M+1] 205.2

Step (b): 3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoic acid methylester

The methyl ester synthesized in Step (a) (12.1 g, 0.059 mol) was dilutedwith acetonitrile (300 mL) and triethylamine (6.6 g, 0.060 mol).Dissolution occurred after stirring at room temperature for 5 minutes.The solution was treated with 4-methoxybenzyl chloride (6.6 g, 0.065mol) and refluxed for overnight. Precipitation occurred on cooling thereaction mixture to room temperature. The solvent was concentrated andthe residue was triturated with ethyl acetate and filtered. The filtratewas washed with aqueous HCl (1M, 50 mL), dried (MgSO4), and concentratedin vacuo. The 2-isomer was isolated analytically pure utilizing silicagel chromatography (elution with dichloromethane) to give the titlecompound (10.5 g, 55%) as a white solid. ¹HNMR (CDCl₃) δ 8.8 (s, 1H),8.3 (d, 1H), 8.1 (d, 1H), 7.5 (t, 1H), 7.2 (d, 2H), 6.9 (d, 2H), 5.7 (s,2H), 3.9 (s, 3H), 3.8 (s, 3H) ppm. Mp 105-106° C.

Step (c): 3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoic acid

The ester prepared in Step (b) (10.4 g, 0.032 mol) was suspended inaqueous tetrahydrofuran (20 mL, 1:1) followed by the addition of lithiumhydroxide monohydrate (4 g, 0.096 mol) in one portion. Dissolutionoccurred after stirring at room temperature for 30 minute. The solutionwas stirred for an additional 16 hours. The THF was concentrated invacuo and the aqueous solution was acidified to pH=1 using concentratedHCl. The resulting precipitate was collected by filtration andrecrystallized from hexane/ethyl acetate to give the title compound (10g, 100%) as a white solid. ¹HNMR (DMSO-d6) δ 8.6 (s, 1H), 8.3 (d, 1H),8.1 (d, 1H), 7.7 (t, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 6.9 (s, 2H), 3.7 (s,3H) ppm.

Step (d): 3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoyl chloride

The carboxylic acid intermediate (10 g, 0.032 mol) from Step (c) wassuspended in dichloromethane followed by the addition of oxalyl chloride(20.4 g, 0.16 mol) and catalytic DMF. The reaction mixture was stirredat room temperature for 3 hours, at which time dissolution was nearlycomplete. The reaction mixture was filtered and concentrated in vacuo.The residue was triturated with petroleum ether and collected byfiltration to give the title compound (9.5 g, 90%) as a white solid.¹HNMR (CDCl₃) δ 8.9 (s, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 8.6 (t, 1H), 7.4(d, 2H), 6.9 (d, 2H), 3.8 (s, 3H) ppm. Mp 122-124° C.

Step (e):4-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid methyl ester

To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (0.22 g,1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) in dichloromethane (20mL) was added the acid chloride (0.33 g, 1.01 mmol) prepared in (e). Thereaction mixture was stirred at room temperature for 16 hour, thendiluted with aqueous HCl (1M, 20 mL). The organic phase was separated,washed with brine, dried (MgSO4), and concentrated in vacuo. The residuewas recrystallized from hexane/ethyl acetate to give a white solid (0.38g, 83%). ¹HNMR (DMSO-d6)

9.4 (t, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (t,1H), 7.5 (d, 2H), 7.4 (d, 2H), 6.9 (d, 2H), 5.9 (s, 2H), 4.5 (d, 2H),3.8 (s, 3H), 3.7 (s, 3H) ppm. Mp 167-168° C.

EXAMPLE 24-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid

The ester (0.065 g, 0.14 mmol) prepared in Example 1, Step (e) wasdiluted with aqueous tetrahydrofuran followed by the addition of lithiumhydroxide monohydrate (0.018 g, 0.4 mmol). Following the experimentalconditions described in (d) yielded the free acid (0.045 g, 71%) as awhite solid. ¹HNMR (DMSO-d6)

12.8 (bs, 1H), 9.4 (t, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.9(d, 2H), 7.7 (t, 1H), 7.4 (dd, 4H), 6.9 (d, 2H), 5.9 (s, 2H), 4.5 (d,2H), 3.7 s, 3H) ppm. Mp 202-205° C.

Replacement of 4-methoxybenzyl chloride in Step (b) of Example 1 with anappropriately substituted alkyl halide and utilizing the experimentalconditions described for Example 1 and Example 2 yielded the followingcompounds:

EXAMPLE 34-({3-[2-(3-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid methyl ester. Mp 153-154° C.

EXAMPLE 44-({3-[2-(3-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid. Mp 204-206° C.

EXAMPLE 54-({3-[2-(4-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid methyl ester. Mp 179-178° C.

EXAMPLE 64-({3-[2-(4-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid. Mp 222-224° C.

EXAMPLE 74-({3-[2-(3-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid methyl ester. Mp 157-155° C.

EXAMPLE 84-({3-[2-(3-Fluoro-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid. Mp 217-219° C.

EXAMPLE 94-{[3-(2-Thiazol-2-ylmethyl-2Htetrazol-5-yl)-benzoylamino]-methyl{-benzoic acid methyl ester. Mp 158-160° C.

EXAMPLE 104-{[3-(2-But-2-enyl-2H-tetrazol-5-yl)-benzoylamino]-methyl}benzoic acidmethyl ester. Mp 107-108° C.

Replacement of methyl 4-(aminomethyl)benzoate hydrochloride in Step (e)of Example 1 with an appropriately substituted amine and utilizing theexperimental conditions described for Example 1 yielded the followingcompounds:

EXAMPLE 113-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-thiazol-2-ylmethyl-benzamideMp 143-145° C.

EXAMPLE 123-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(4-morpholin-4-ylmethyl-benzyl)-benzamideMp 161-162° C.

EXAMPLE 13N-(3-Chloro-4-fluoro-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamideMp 150-151° C.

EXAMPLE 143-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(3-trifluoromethyl-benzyl)-benzamideMp 162-163° C.

EXAMPLE 15N-2,1,3-Benzothiadiazol-5-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamideMp 207-208° C.

EXAMPLE 163-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-methoxy-pyridin-4-ylmethyl)-benzamideMp 166-169° C.

EXAMPLE 17 N-Benzyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamideMp 169-170° C.

EXAMPLE 183-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-pyridin-4-ylmethyl-benzamideMp 163-164° C.

EXAMPLE 19N-1,3-Benzodioxol-5-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide

LC/MS: MW 443.46, 94.69% purity

EXAMPLE 203-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-pyridin-4-yl-ethyl)-benzamide

LC/MS: MW 414.46, 100% purity

EXAMPLE 213-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(2-trifluoromethyl-benzyl)-benzamide

LC/MS: MW 467.45, 94.93% purity

EXAMPLE 22N-Isopropyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide

LC/MS: MW 351.41, 96.37% purity

EXAMPLE 23N-(2,3-Difluoro-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide

LC/MS: MW 435.43, 100% purity

EXAMPLE 24N-Furan-2-ylmethyl-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide

LC/MS: MW 389.41, 100% purity

EXAMPLE 253-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-N-(1-phenyl-ethyl)-benzamide

LC/MS: MW 427.51, 100% purity

EXAMPLE 26N-(4-Methoxy-benzyl)-3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamideMp 159-160° C.

Replacement of 4-methoxybenzyl chloride and methyl4-(aminomethyl)benzoate hydrochloride in Steps (b) and (e) respectivelyof Example 1 with an appropriately substituted alkyl halide and amine,and utilizing the experimental conditions described for Example 1,yielded the following compounds:

EXAMPLE 27 N-Benzyl-3-(2-but-2-enyl-2H-tetrazol-5-yl)-benzamide. Mp100-101° C.

EXAMPLE 283-(2-But-2-enyl-2H-tetrazol-5-yl)-N-(3-methoxy-benzyl)-benzamide

Elem. Anal. Calcd. For C₂₀H₂₁N₅O₂: C, 66.10%; H, 5.82%; N, 19.27%;Found: C, 66.00%; H, 5.78%; N, 19.23%.

EXAMPLE 29 N-Benzyl-3-[2-(4-cyano-benzyl)-2H-tetrazol-5-yl]-benzamide.Mp 191-192° C.

EXAMPLE 304-(5-{3-[(Pyridin-4-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid. TFA salt Mp 222° C. dec.

EXAMPLE 314-(5-{3-[(Pyridin-3-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid. TFA salt Mp 253° C. dec.

EXAMPLE 324-(5-{3-[(Methyl-pyridin-3-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid. TFA salt Mp 235° C. dec.

EXAMPLE 334-(5-{3-[(2-Methoxy-pyridin-4-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid. TFA salt Mp 228° C. dec.

EXAMPLE 34N-(4-Fluoro-benzyl)-2-methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamideStep (a): 5-(3-Bromo-4-methoxy-phenyl)-2H-tetrazole

The same procedure was used to form the tetrazole as that which wasdescribed in Step (a) of Example 1. Yield: 9.9 g, 97%. ¹HNMR (DMSO-d6)

7.8 (s, 1H), 7.6 (d, 1H), 6.9 (d, 1H), 3.5 (s, 3H) ppm.

Step (b): 5-(3-Bromo-4-methoxy-phenyl)-2-(4-methoxy-benzyl)-2H-tetrazole

The tetrazole synthesized in Step (a) was alkylated using theexperimental conditions described in Step (b) of Example 1. Yield: 8.6g, 59%. ¹HNMR (CDCl₃)

8.3 (s, 1H), 8.0 (d, 1H), 7.4 (d, 2H), 7.0 (d, 1H), 6.9 (d, 2H), 5.7 (s,2H), 3.9 (s, 3H), 3.7 (s, 3H) ppm.

Step (c): 2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoicacid methyl ester

The tetrazole (4 g, 0.011 mol) prepared in Step (b) was added to aglass-lined reactor containing triethylamine (0.73 g, 0.03 mol),diphenylphosphinylpropane (0.66 g, 1.6 mmol), palladium (II) acetate(0.24 g, 1.1 mmol), and anhydrous methanol (70 mL). The reaction mixturewas heated to 100° C. under 500 psi carbon monoxide for 12 hours. Thereaction mixture was filtered and thoroughly washed withtetrahydrofuran. The filtrate was concentrated in vacuo and the residuewas recrystallized from hexane/ethyl acetate to give white crystallineneedles (1.6 g, 43%). Mp 110-111° C. ¹HNMR (CDCl3)

8.5 (s, 1H), 8.2 (d, 1H), 7.8 (m, 1H), 7.3-7.5 (m, 3H), 7.1 (d, 1H), 6.9(d, 2H), 5.7 (s, 2H), 4.0 (s, 3H), 3.9 (s, 3H), 3.8 (s, 3H) ppm.

Step (d): 2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoicacid

The ester (0.91 g, 2.57 mmol) obtained in Step (c) was converted to thecorresponding carboxylic acid utilizing reaction conditions described instep c of Example 1. Yield: 0.57 g, 65%. ¹HNMR (CDCl3)

8.9 (s, 1H), 8.3 (d, 1H), 7.4 (d, 2H), 7.2 (d, 1H), 6.9 (d, 2H), 5.7 (s,2H), 4.1 (s, 3H), 3.8 (s, 3H) ppm.

Step (e): 2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylchloride

The acid chloride was prepared from the carboxylic acid (0.52 g, 1.54mmol, Step (d)) using reaction conditions previously described for stepd of Example 1. The crude product (0.57 g, tan solid) was used withoutfurther characterization.

Step (f):N-(4-Fluoro-benzyl)-2-methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzamide

The crude acid chloride (0.2 g, 0.56 mmol) obtained in Step (e) wastaken up in dichloromethane (2 mL) and added dropwise to a solution of4-fluorobenzylamine (0.07 g, 0.56 mmol) and triethylamine (0.062 g, 0.61mmol) in dichloromethane (3 mL). The reaction mixture was stirred atroom temperature for 16 hours, then diluted with aqueous HCl (1M, 5 mL).The organic phase was separated, dried (MgSO4), and concentrated invacuo. The resulting solid was triturated with petroleum ether/diethylether (1:1) to yield a pale yellow solid (0.18 g, 72%). ¹HNMR (CDCl3)

8.9 (s, 1H), 8.3 (d, 1H), 8.1 (bs, 1H), 7.4 (d, 2H), 7.3 (m, 2H), 7.1(m, 3H), 6.9 (d, 2H), 5.7 (s, 2H), 4.7 (d, 2H), 4.0 (s, 3H), 3.8 (s, 3H)ppm. Mp 156-158° C.

Replacement of 4-fluorobenzyl amine in Step (f) of Example 27 with anappropriately substituted amine yielded the corresponding tetrazoleamide derivatives:

EXAMPLE 354-({2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid). Mp 177-178° C.

EXAMPLE 364-({2-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid. Mp 207-209° C.

EXAMPLE 372-Methoxy-5-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-N-(4-trifluoromethyl-benzyl)-benzamide.Mp 188-190° C.

EXAMPLE 38 Benzyl{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzyl}-amine hydrochlorideStep (a): {3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-phenyl}-methanol

The acid chloride (2.5 g, 7.6 mmol) prepared in Step (d) of Example 1was added to a suspension of lithium aluminum hydride (“LAH”) (0.58 g,25 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. The reaction mixturegradually warmed to room temperature over two hours. Aqueous HCl wasadded dropwise to quench excess LAH. The mixture was diluted with ethylacetate and filtered through Celite. The filtrate was washed with brine,dried (MgSO4), and concentrated. The resulting viscous liquid wastriturated with hexane/diethyl ether to yield a pale yellow solid (1.9g, 84%). Mp 70-72° C.

Step (b): 5-(3-Bromomethyl-phenyl)-2-(4-methoxy-benzyl)-2H-tetrazole

The alcohol (1 g, 3.37 mmol) of Step (a) was dissolved indichloromethane (25 mL) and added dropwise at room temperature to asolution of phosphorous tribromide (1 g, 3.7 mmol) in dichloromethane(75 mL). The solution was stirred for 16 hours, then concentrated invacuo. The residue obtained was triturated with hexane and collected byfiltration to yield a white solid (1.17 g, 92%). ¹HNMR (CDCl3)

8.2 (d, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (d, 2H), 6.8 (d, 2H), 5.8 (s,2H), 4.5 (s, 2H), 3.7 (s, 3H) ppm.

Step (c): Benzyl{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzyl}-amine hydrochloride

The alkyl halide (0.42 g, 1.06 mmol) prepared in Step (b) was dissolvedin tetrahydrofuran (20 mL) followed by the addition of benzylamine (0.24g, 2.2 mmol). The solution was refluxed for 16 hours, cooled to roomtemperature, and concentrated in vacuo. The crude product was trituratedwith ethyl acetate, filtered, and the filtrate concentrated. The freebase was isolated pure as a colorless liquid using silica gelchromatography (elution with dichloromethane/THF). The compound wastaken up in diethyl ether and precipitated as the HCl salt upontreatment with gaseous HCl. The solid (0.25 g, 57%) was collected byfiltration. Mp 159-161° C.

If benzylamine in Step (c) of Example 38 is replaced with anappropriately substituted amine or alcohol, the following compounds willbe obtained.

EXAMPLE 39(4-Methanesulfonyl-benzyl)-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-benzyl}-amine

EXAMPLE 404-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzylamino}-methyl)-benzoicacid

EXAMPLE 414-{3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzyloxymethyl}-benzoicacid

EXAMPLE 424-{3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzyloxy}-benzoic acid

EXAMPLE 434-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic acid

Step (a): 5-(3-Iodo-phenyl)-2H-tetrazole

The 3-iodobenzonitrile (3.6 g, 16.6 mmol) was converted to thecorresponding tetrazole (4.1 g, 91%) utilizing reaction conditionspreviously described in Step (a) of example 1. CI-MS: C₇H₅₁N₂ [M+1]273.0.

Step (b): 4-[5-(3-Iodo-phenyl)-tetrazol-2-ylmethyl]-benzoic acidtert-butyl ester

The tetrazole (4 g, 14.7 mmol) prepared in Step (a) was alkylated usingthe reaction conditions previously described in Step (b) of Example 1 togive analytically pure 2-regioisomer (3 g, 44%) and the 1-regioisomer(0.54 g, 8%) respectively. ¹HNMR (CDCl3) 2-regioisomer δ 8.5 (s, 1H),8.1 (d, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.4 (d, 2H), 7.2 (m, 2H), 5.8 (s,2H), 1.6 (s, 9H) ppm. ¹HNMR (CDCl3) 1-regioisomer δ 8.0 (d, 2H), 7.9 (d,2H), 7.5 (d, 1H), 7.3-7.1 (m, 3H), 5.6 (s, 2H) 1.6 (s, 9H) ppm.

Step (c): 4-[5-(3-Iodo-phenyl)-tetrazol-2-ylmethyl]-benzoic acid

The ester (2.5 g, 5.41 mmol) prepared in Step (b) was suspended indichloromethane (20 mL) followed by the addition of trifluoroacetic acid(5 mL). The solution was stirred for 16 hours at 25° C., thenconcentrated in vacuo. The resulting white solid was triturated withhexane/diethyl ether and the carboxylic acid (2.1 g, 100%) was collectedby filtration. Mp 241-242° C.

Step (d):4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic acid

The iodo derivative (1 g, 2.46 mmol) prepared in Step (c) was dissolvedin dimethylformamide (10 mL) followed by the addition ofdiisopropylethylamine (1.3 g, 9.8 mmol), copper (I) iodide (0.17 g, 0.89mmol), 3-phenyl-1-propyne (0.40 g, 3.4 mmol), andbis(triphenylphosphine) palladium (II) dichloride (0.34 g, 0.49 mmol).The reaction mixture was stirred at 50° C. for 4 hours under anatmosphere of N₂. The dark reaction mixture was cooled to roomtemperature and diluted with equal volumes of ethyl acetate and aqueousHCl. The organic phase was separated, washed with brine, dried (MgSO4)and concentrated in vacuo. The liquid obtained was purified using silicagel chromatography (elution with dichloromethane/tetrahydrofuran) togive a cream colored solid (0.37 g, 38%). Mp 195-198° C. ¹HNMR (DMSO-d6)δ 13.0 (bs, 1H), 8.0-7.9 (m, 4H), 7.7-7.2 (m, 9H), 6.1 (s, 2H), 3.9 (s,2H) ppm.

If 3-phenyl-1-propyne in Step (d) of Example 43 is replaced with anappropriately 3-substituted propyne, the following compounds will beobtained.

EXAMPLE 444-{5-[3-(3-Imidazol-1-yl-prop-1-ynyl)-phenyl]-terazol-2-ylmethyl}-benzoicacid

EXAMPLE 454-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid

EXAMPLE 464-{5-[3-(3-Methyl-3-phenyl-but-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoicacid

The compounds of Example Table A below were prepared according to themethods illustrated above in Schemes 6 to 10.

EXAMPLE TABLE A

Example Characterizing No. R¹ Q R²¹ R²² Data A1 Benzyl(“Bn”)

COOH H MS: m/z (APCI,AP+) 439 [M]⁺ A2 Phenyl(“Ph”)

COOH H MS: m/z (APCI,AP+) 425 [M]⁺ A3 Ph

COOC(CH₃)₃ H MS: m/z (APCI,AP+) 479 [M]⁺ A4 Ph

COOH H MS: m/z (APCI,AP+) 424 [M]⁺ A5 Ph

F F MS: m/z (APCI,AP+) 416 [M]⁺ A6 4-CH₃O-Ph

COOC(CH₃)₃ H MS: m/z (APCI,AP+) 510 [M]⁺ A7 4-CH₃O-Ph

COOH H MS: m/z (APCI,AP+) 454 [M]⁺ A8 4-CH₃O-Ph

F F MS: m/z (APCI,AP+) 446 [M]⁺ A9 4-CH₃O-Ph

COOH H MS: m/z (APCI,AP+) 470 [M]⁺ A10 4-Cl-Ph

COOH H MS: m/z (APCI,AP+) 490 [M]⁺

The compounds of Example Table A have the following chemical names(Example No.):

-   4-{5-[3-(5-Benzyl-[1,3,4]oxadiazol-2-yl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (A1);-   4-{5-[3-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (A2);-   4-{5-[3-(5-Phenyl-oxazol-2-yl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid tertiary butyl ester (A3);-   4-{5-[3-(5-Phenyl-oxazol-2-yl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (A4);-   2-(3,4-Difluoro-benzyl)-5-[3-(5-phenyl-oxazol-2-yl)-phenyl]-2H-tetrazole    (A5);-   4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid tertiary butyl ester (A6);-   4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (A7);-   2-(3,4-Difluoro-benzyl)-5-{3-[5-(4-methoxy-phenyl)-oxazol-2-yl]-phenyl}-2H-tetrazole    (A8);-   4-(5-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (A9); and-   4-(5-{3-[5-(4-Chloro-phenyl)-oxazol-2-yl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (A10).

EXAMPLE B1a Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-yl)-benzoicacid methyl ester

Using the procedure from Example B2a below and4-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazinocarbonyl)-benzoicacid methyl ester from Preparation 9 as starting material 0.21 g (48%)desired product was obtained. MS: m/z (APCI, AP+) 454 [M^(.)]⁺.

EXAMPLE B1 Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-yl)-benzoicacid

Using the procedure from Example B2 below and4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-yl)-benzoicacid methyl ester from Example B1a as starting material 0.09 g (45%)desired product was obtained. MS: m/z (APCI, AP+) 440 [M^(.)]⁺. NMR:DMSO ¹H δ (ppm) 3.81 (3H, s); 7.07-7.09 (2H, m); 7.68-7.83 (5H, m);8.15-8.17 (2H, m); 8.25-8.33 (4H, m); 8.71-8.72 (1H, m).

EXAMPLE B2a Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoicacid methyl ester

0.24 g (0.49 mmol) of4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoicacid methyl ester from Preparation 8 was dissolved in about 10 mL ofpoly phosphoric acid. The mixture was stirred at 90-100° C. for 1 hourbefore allowing to cool to room temperature. Water was added and theproduct was extracted with 1:1:1 EtOAC/THF/Et₂O (2×). The extracts werecombined and washed with saturated aqueous NaCl solution then driedMgSO₄. Slurried solid product in hot EtOAc and filtered. Dried in vacuumoven overnight at 70° C. to obtain 0.13 g (57%) desired product.

MS: m/z (APCI, AP+) 468 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.80 (3H, s); 3.3.83 (3H, s); 7.04-7.07 (2H, m);7.54-7.56 (2H, m); 7.57-7.79 (4H, m); 7.91-7.96 (2H, m); 8.05-8.08 (1H,m); 8.25-8.27 (1H, m); 8.52-8.53 (1H, M).

EXAMPLE B2 Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoicacid

A solution of 0.25 g (0.53 mmol)4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoicacid methyl ester from Example B2a in a 5:2:1 mixture ofTHF/methanol/water was added 1.0 mL (1.0 mmol) 1N NaOH. The mixture wasstirred 14 hours at room temperature before concentrating on a rotaryevaporator. Partitioned between ether and water. Separated layers andacidified aqueous layer with 6M HCl. Extracted aqueous layer with 1:1Et₂O/EtOAc (2×), combined organic layers and wash with saturated aqueousNaCl solution and dried (MgSO₄). Obtained a solid from MeOH. Filter anddry in a vacuum oven overnight at room temperature to provide 0.068 g(28%) desired product.

MS: m/z (APCI, AP+) 454 [M^(.)]⁺

NMR: DMSO ¹H δ (ppm) 3.81 (3H, s); 4.49 (2H, s); 7.04-7.08 (2H, m);7.72-7.79 (3H, m); 7.88-7.99 (2H, m); 8.05-8.08 (1H, m); 8.22-8.28 (1Hm); 8.53-8.54 (1H, m).

EXAMPLE B3a Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid methyl ester

To a suspension of 0.25 g (0.51 mmol)4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoicacid methyl ester from Preparation 8 in 10 mL dry dioxane was added P₂S₅in one portion. The resulting mixture was warmed to 50° C. for 1 hourbefore cooling to room temperature and adding about 20 mL water. Stirred2 hours and then filtered off solid product. Triturated in hot MeOH andfiltered. Dissolved in THF and filtered through a plug of flash silicagel with THF eluent. Concentration gave 0.18 g (73%) desired product.Used directly in the procedure of Example B3 without characterization.

EXAMPLE B3 Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid

Using the procedure from Example B2 and 0.18 g (0.37 mmol)4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid methyl ester from Example B3a as starting material 0.079 g (46%)desired product was obtained. MS: m/z (APCI, AP+) 470 [M^(.)]⁺. NMR:DMSO ¹H δ (ppm) 3.79 (3H, s); 4.63 (2H, s); 7.05-7.08 (2H, m); 7.50-7.52(2H, m); 7.67-7.79 (4H, M); 7.81-8.02 (2H, m); 8.02-8.04 (2H, m);8.17-8.19 (1H, m); 8.20-8.21 (1H, m); 8.52-8.53 (1H, m).

EXAMPLE B4a Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid methyl ester

Using the procedure from Example B3a and 0.33 (0.65 mmol)4-[2-[N′-{3-[5-(4-methoxy-phenyl)-thiazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoicacid methyl ester from Preparation 14 as starting material 0.18 g (55%)desired product was obtained. MS: m/z (APCI, AP+) 500 [M^(.)]+NMR: DMSO¹H δ (ppm) 3.79 (3H, s); 3.83 (3H, s); 4.64 (2H, s); 7.01-7.03 (2H, m);7.37-7.67 (5H, m); 7.91-8.22 (4H, m); 8.23 (1H, s); 8.43-8.44 (1H, m).

EXAMPLE B4 Synthesis of4-(5-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid

Using the procedure from Example B3 and 0.16 g (0.32 mmol)4-(5-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoicacid methyl ester from Example B4a 0.023 g (16%) desired product wasobtained. MS: m/z (APCI, AP−) 487 [M^(.)]⁻. NMR: DMSO ¹H δ (ppm) 3.79(3H, s); 4.62 (2H, s); 7.01-7.03 (2H, m); 7.45-7.88 (5H, m); 7.90-8.22(4H, m); 8.24 (1H, s); 8.43-8.44 (1H, m).

The compounds of Example Table B below were prepared according to themethods illustrated above in Schemes 6 to 10 and the preparations andprocedures.

EXAMPLE TABLE B

Example Characterizing No. R²³ X V R² Data B1 CH₃O O

See above B2 CH₃O O

See above B3 CH₃O O

See above B4 CH₃O S

See above

The compounds of Example Table B have the following chemical names(Example No.):

-   4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-yl)-benzoic    acid (B1);-   4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]oxadiazol-2-ylmethyl)-benzoic    acid (B2);-   4-(5-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid (B3); and-   4-(5-{3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid (B4).

The compounds of Example Table C below were prepared according to themethods illustrated above in Schemes 6 to 10 or Schemes 1 to 5.

EXAMPLE TABLE C

Example No. R²³ V R² Characterizing Data C1 H

MS: m/z (APCI,AP+) 381 [M]⁺ C2 F

MS: m/z (APCI,AP+) 429 [M]⁺ C3 H

MS: m/z (APCI,AP+) 395 [M]⁺ C4 F

Mp 210-212° C.

The compounds of Example Table C have the following chemical names(Example No.):

-   4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-[1,3,4]oxadiazol-2-yl}-benzoic    acid (C1);-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-[1,3,4]thiadiazol-2-ylmethyl)-benzoic    acid (C2);-   4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-[1,3,4]oxadiazol-2-ylmethyl}-benzoic    acid (C3); and-   4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (C4).

The compounds of Example Table D were prepared as described below.

EXAMPLE TABLE D

Example No. R²³ R²¹ Characterizing Data D1 F SO₃H See below D2 F PO₃H₂See below D3 F OCH₂COOH See below D4 H S(O)₂NH₂ Mp 158-159° C. D5 FS(O)₂CH₃ Mp 101-104° C. D6 H CH₂NH₂ 1H NMR (400 MHz, DMSO-D) d ppm8.08(s, br, 2H), 8.00 (m, 2H), 7.56 (m, 2H), 7.46 (s, 4H), 7.37 (m, 4H),7.25 (m, 1H), 6.00 (s, 2H), 4.01 (s, 2H), 3.91 (s, 2H) D7 HCH₂N(H)C(O)(CH₂)₂CH₃ 1H NMR (400 MHz, DMSO-D) d ppm 8.25 (t, br, 1H),8.00 (m, 2H), 7.55 (m, 2H), 7.37 (m, 6H), 7.24 (m, 3H), 5.94 (s, 2H),4.22 (d, 2H), 3.91 (s, 2H), 2.07 (t, 2H), 1.50 (m, 2H), 0.82 (t, 3H). D8H CH₂N(H)C(O)CH₃ 1H NMR (400 MHz, DMSO-D) d ppm 8.29 (t, br, 1H), 8.00(m, 2H), 7.55 (m, 2H), 7.37 (m, 6H), 7.24 (m, 3H), 5.94 (s, 2H), 4.20(d, 2H), 3.91 (s, 2H), 1.82 (s, 3H).

EXAMPLE D1 Synthesis of4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzenesulfonicacid Step (a): 5-(3-bromophenyl)-2H-tetrazole

A mixture of 3-bromobenzonitrile (30.00 g, 164.8 mmol) in toluene (300mL) was treated with triethylamine hydrochloride (68.05 g, 494.4 mmol)and sodium azide (32.14 g, 494.4 mmol) and the reaction mixture heatedto reflux over night. Cooled to room temperature, diluted with water(300 mL), the layers were separated, and the aqueous portion acidifiedto pH 1 using concentrated HCl. The precipitated solid was collected byfiltration, washed with water, and dried to give 34.96 g of product(94.3% yield).

NMR (DMSO-d₆); 9.19-8.18 (m, 1H), 8.04-8.02 (dd, 1H), 7.79-7.76 (m, 1H),7.57-7.53 (t, 1H)

MS (APCI) M+1=224.9

Mp 151.0-152.0° C.

Step (b): 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]benzenesulfonic acid,sodium salt

A solution of 5-(3-bromophenyl)-2H-tetrazole (0.8 g, 3.55 mmol) in DMF(15 mL) was treated with triethylamine (0.6 mL, 4.25 mmol) and thereaction mixture stirred at room temperature for 30 minutes. To this wasadded sodium 4-bromomethylbenzenesulfonate (1.17 g, 4.27 mmol) and thereaction mixture stirred over night at room temperature. The reactionmixture was evaporated to dryness, treated with acetic acid, andevaporated to dryness again. The white solid was triturated with ethylacetate/methanol 4:1, the solid was collected by filtration, washed withethyl acetate/methanol 4:1, and dried under house vacuum to afford 1.10g of white solid (78.3% yield).

NMR (DMSO-d₆); 8.14 (m, 1H), 8.04-8.01 (d, 1H), 7.74-7.71 (m, 1H),7.62-7.60 (d, 2H), 7.51-7.48 (t, 1H), 7.36-7.34 (d, 2H), 5.99 (s, 2H)

MS (APCI) M−1=395.0

mp. >250.0° C.

Step (c):4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)benzene-sulfonicacid

A suspension of 4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]benzenesulfonicacid, sodium salt (0.50 g, 1.27 mmol) in DMF (3 mL) was treated withdiisopropylethylamine (0.88 mL, 5.1 mol), palladiumtetrakis(triphenylphosphine) (“Pd(PPh₃)₄”, 0.29 g, 0.25 mmol), CuI(cat), and 1-fluoro-4-prop-2-ynyl-benzene (0.42 g, 3.1 mmol), and themixture degassed with nitrogen. The reaction mixture was heated in themicrowave for 15 minutes at 100° C., cooled to room temperature, pouredinto 1N HCl, extracted with EtOAc, washed with brine, dried over MgSO₄,and evaporated onto silica gel. The mesh was purified on a 3.5×15 cmsilica gel column eluted with ethyl acetate (“EtOAc”)-methanol (“MeOH”)4:1 with 1% acetic acid (“AcOH”). Evaporation and trituration with etherafforded 0.052 g of orange solid (8.26% yield) NMR (DMSO-d₆); 8.03-7.99(m, 1H), 7.61-7.51 (m, 6H), 7.46-7.42 (dd, 1H), 7.36-7.33 (d, 2H),7.19-7.15 (t, 2H), 5.98 (s, 2H), 3.90 (s, 2H)

MS (APCI) small M+1=449.0

EXAMPLE D2 Synthesis of[4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenyl]-phosphonicacid Step (a): {4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]benzyl}phosphonic acid dimethyl ester

To a solution of 5-(3-bromophenyl)-2H-tetrazole (0.5 g, 2.22 mmol) inDMF (15 mL) was added cesium carbonate (0.94 g, 2.89) and the mixturestirred at room temperature for 15 minutes. To this was added(4-bromo-methylbenzyl) phosphonic acid dimethyl ester (0.85 g, 3.05mmol) and the reaction mixture stirred over night at room temperature.The reaction mixture was diluted with ethyl acetate, washed with water,brine, dried over MgSO₄, filtered, and the evaporated to dryness.

The light yellow oil was dissolved in chloroform and evaporated ontosilica gel. The silica gel mesh was purified on a 3.5×15 cm silica gelcolumn eluted with ethyl acetate/methanol 9:1. Evaporation of theappropriate fractions followed by drying, afforded 0.85 g of gummy oil(90.4% yield). The light yellow oil was purified again on a 5×15 cmsilica gel column eluted with ethyl acetate. Drying afforded 0.64 g ofcolorless oil.

NMR (CDCl₃); 8.28-8.27 (m, 1H), 8.07-8.05 (dd, 1H), 7.58-7.56 (m, 1H),7.38-7.30 (m, 6H), 5.77 (s, 2H), 3.68 (s, 3H), 3.66 (s, 3H)

MS (APCI) no M+1 peak

Step (b): [4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)benzyl]-phosphonic acid dimethylester

This reaction was carried out as described in Example D1, Step (c) using{4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]benzyl}phosphonic aciddimethyl ester (0.61 g, 1.33 mmol) in place of4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]benzenesulfonic acid, sodiumsalt. This afforded 0.27 g of yellow oil (42.6% yield).

NMR (CDCl₃); 8.21 (s, 1H), 8.07-8.04 (dd, 1H), 7.67-7.64 (m, 1H),7.42-7.29 (m, 8H), 7.05-7.00 (t, 1H), 5.77 (s, 2H), 3.80 (s, 2H), 3.68(s, 3H), 3.65 (s, 3H)

MS (APCI) no M+1 or M−1 peak

Step (c): [4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)benzyl]-phosphonic acid

A solution of [4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)benzyl]phosphonic acid dimethylester (0.25 g, 0.53 mmol) in methylene chloride (15 mL) was cooled to 0°C., then treated with trimethylsilyliodide (0.23 mL, 1.33 mmol). Thereaction mixture was removed from the cooling bath and stirred at roomtemperature for 1 hour. The reaction mixture was concentrated on therotary evaporator without heat and the residue was treated withchloroform. The resulting solid was collected by filtration, washed withchloroform, triturated with hot ether, collected by filtration anddried. High performance liquid chromatography (“HPLC”) indicates thatthis solid is 65% pure.

The solid was heated in hexanes/ethyl acetate 1:1, cooled to roomtemperature, collected by filtration and dried. The impure solid waswashed with a small amount of methanol, collected, washed with methanoland dried. This afforded 0.0766 g of yellow solid.

NMR (DMSO-d₆); 8.03-7.98 (m, 2H), 7.59-7.51 (m, 2H), 7.46-7.42 (m, 2H),7.33-7.31 (d, 2H), 7.26-7.24 (m, 2H), 7.19-7.15 (m, 2H), 5.93 (s, 2H),3.90 (s, 2H), 2.96-2.90 (d, 2H)

MS (APCI) M+1=463.1

EXAMPLE D3 Synthesis of[4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenoxy]-aceticacid Step (a): {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}aceticacid tert-butyl ester

This reaction was carried out as described in Example D2, Step (a) using5-(3-bromophenyl)-2H-tetrazole (0.87 g, 2.89 mmol) and(4-bromomethylphenoxy)acetic acid tert-butyl ester (0.50 g, 2.22 mmol)in place of (4-bromo-methylbenzyl) phosphonic acid dimethyl ester. Thisafforded 0.85 g of light oil (84.6% yield) NMR (CDCl₃); 8.28 (s, 1H),8.07-8.05 (d, 1H), 7.58-7.55 (d, 1H), 7.38-7.31 (m, 3H), 6.90-6.88 (d,2H), 5.72 (s, 2H), 4.50 (s, 2H), 1.48 (s, 9H)

MS (APCI) M+1=445.0

Step 2:[4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)phenoxy]aceticacid tert-butyl ester

This reaction was carried out as described in Example D1, Step (c) using1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and{4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butylester (0.30 g, 0.67 mmol) in place of4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodiumsalt. This afforded 0.23 g of the product (68.5% yield).

NMR (CDCl₃); 8.21 (s, 1H), 8.07-8.05 (d, 1H) 7.52-7.49 (m, 1H),7.42-7.35 (m, 4H), 7.05-6.90 (t, 2H), 6.89-6.87 (d, 3H), 5.72 (s, 2H),4.49 (s, 2H), 3.81 (s, 2H), 1.48 (s, 9H)

MS (APCI) M+1 (-t-Bu)=443.1

Step 3:[4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)phenoxy]aceticacid

A solution of[4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl)phenoxy]-aceticacid tert-butyl ester (0.19 g. 0.38 mmol) in trifluoroacetic acid(“TFA”) (6 mL) was stirred at room temperature for 75 minutes, thenevaporated to dryness. The residue was triturated with ether,evaporated, triturated again with ether/hexanes, evaporated, thentriturated with hexanes/ethyl acetate 3:1. The solid was collected byfiltration, washed with hexanes/ethyl acetate 3:1 and dried to give0.1047 g of orange solid (59.11% yield).

NMR (DMSO-d₆) 12.99 (bs, 1H), 8.02-7.98 (m, 2H), 7.56-7.51 (m, 2H),7.46-7.42 (m, 2H), 7.37-7.36 (d, 2H), 7.19-7.17 (t, 2H), 6.92-6.90 (d,2H), 5.89 (s, 2H), 4.64 (bs, 2H), 3.90 (s, 2H)

MS (APCI) M−1=441.0

mp 158.2-159.6° C.

Certain compounds of Example Table D have the following chemical names(Example No.):

-   4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzenesulfonamide    (D4);-   5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-2-(4-methanesulfonyl-benzyl)-2H-tetrazole    (D5);-   4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzylamine    (D6);-   N-(4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzyl)-butyramide    (D7); and-   N-(4-{5-[3-(3-Phenyl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzyl)-acetamide    (D8).

The compound of Example E1 was prepared by adapting the methodsdescribed above.

EXAMPLE E14-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoicacid trifluoroacetic acid salt (mp 202-205° C.)

Additional compounds of this invention were prepared by adapting themethods described above and are shown below in Example Table F.

EXAMPLE TABLE F

Example No. R²³ S R²¹ Characterizing Data F1¹

CH COOH Mp 222° C. (dec) F2¹

CH COOH Mp 253° C. (dec) F3

N S(O)₂CH₃ Mp 143-144° C. F4

N S(O)₂CH₃ Mp 178-179° C. F5

N —C≡N Mp 178-179° C. F6

N S(O)₂CH₃ Mp 145-146° C. F7

N S(O)₂CH₃ Mp 174-175° C. F8

N S(O)₂CH₃ Mp 100-103° C. F9

N S(O)₂CH₃ Mp 147-150° C. F10

N S(O)₂CH₃ Mp 150-152° C. F11

N S(O)₂CH₃ Mp 173-174° C. F12

N COOH Mp 193-194° C. (1) trifluoroacetic acid salt

The compounds of Example Table F have the following chemical names(Example No.):

-   4-(5-{3-[(Pyridin-4-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; compound with trifluoro-acetic acid (F1);-   4-(5-{3-[(Pyridin-3-ylmethyl)-carbamoyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid; compound with trifluoro-acetic acid (F2);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid (pyridin-4-ylmethyl)-amide (F3);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid (pyrimidin-5-ylmethyl)-amide (F4);-   4-[2-(4-Cyano-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic acid

(pyridin-4-ylmethyl)-amide (F5);

-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid 4-methoxy-benzylamide (F6);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid (pyridin-3-ylmethyl)-amide (F7);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid 4-phenoxy-benzylamide (F8);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid indan-1-ylamide (F9);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid 3,4-dichloro-benzylamide (F10);-   4-[2-(4-Methanesulfonyl-benzyl)-2H-tetrazol-5-yl]-pyridine-2-carboxylic    acid 4-pyrazol-1-yl-benzylamide (F11); and-   4-{5-[2-(4-Fluoro-benzylcarbamoyl)-pyridin-4-yl]-tetrazol-2-ylmethyl}-benzoic    acid (F12).

Additional compounds of this invention were prepared by adapting themethods described above and are shown below in Example Table G.

EXAMPLE TABLE G

Example No. R²³ Characterizing Data G1 Ph MP 226-228° C. G2 Ph-CH₂CH₂—MP 198-199° C. G3 (CH₃)₂CH₂CH₂— MP 192-193° C. G4

1H NMR (400 MHz, CHLOROFORM-D)d ppm 4.8 (s, 2 H) 5.8 (s, 2 H) 6.9 (m, 4H)7.4 (m, 4 H) 8.0 (m, 3 H) 8.1 (s, 1 H) G5

1H NMR (400 MHz, DMSO-D6) d ppm 5.4(s, 2 H) 6.1 (s, 2 H) 7.5 (d, J = 8.5Hz, 2 H)7.6 (t, J = 7.7 Hz, 1 H) 7.7 (dt, J = 1.5 Hz, 2H) 7.9 (s, 1 H)7.9 (d, J = 8.3 Hz, 2 H) 8.1(m, 2 H) 9.2 (s, 1 H) G6

1H NMR (400 MHz, CHLOROFORM-D)d ppm 5.0 (s, 2 H) 5.8 (s, 2 H) 6.9 (d, J= 7.1Hz, 2 H) 7.4 (m, 4 H) 7.9 (dd, J = 7.9 Hz, 6H) 8.0 (d, J = 7.6 Hz,1 H) 8.1 (s, 1 H) G7

1H NMR (400 MHz, CHLOROFORM-D)d ppm 5.1 (s, 2 H) 5.7 (s, 2 H) 7.2 (s, 1H)7.2 (d, J = 7.3 Hz, 1 H) 7.3 (m, 4 H) 7.4 (d,J = 7.8 Hz, 2 H) 7.6 (s,2 H) 7.9 (d, J = 8.1 Hz,2 H) 8.0 (d, J = 7.8 Hz, 1 H) 8.1 (s, 1 H)8.5(s, 1 H) G8 Ph—C(CH₃)H—

The compounds of Example Table G have the following chemical names(Example No.):

-   4-[5-(3-Phenylethynyl-phenyl)-tetrazol-2-ylmethyl]-benzoic acid    (G1);-   4-{5-[3-(4-Phenyl-but-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (G2);-   4-{5-[3-(4-Methyl-pent-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (G3);-   4-(5-{3-[3-(4-Fluoro-phenoxy)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (G4);-   4-{5-[3-(3-Imidazol-1-yl-prop-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (G5);-   4-(5-{3-[3-(4-Oxo-4H-pyridin-1-yl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (G6);-   4-(5-{3-[3-(4-Phenyl-imidazol-1-yl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoic    acid (G7); and-   4-{5-[3-(3-Phenyl-but-1-ynyl)-phenyl]-tetrazol-2-ylmethyl}-benzoic    acid (G8).

Additional compounds of this invention were prepared by adapting themethods described above and are shown below in Example Table G.

EXAMPLE TABLE H

Example No. R²³ Characterizing Data H1 Ph-CH₂— MP 211-213° C. H24-fluoro-benzyl See below H3

1H NMR (400 MHz, DMSO-D6) d ppm 5.5(s, 2 H) 6.1 (s, 2 H) 7.5 (d, J = 8.1Hz, 3 H)7.9 (d, J = 7.6 Hz, 3 H) 8.5 (s, 1 H) 8.9 (s, 1H) 9.2 (s, 2 H)H4 4-methoxy-benzyl 1H NMR (400 MHz, CHLOROFORM-D) dppm 3.8 (s, 2 H) 3.8(s, 3 H) 5.8 (s, 2 H) 6.9(d, J = 8.5 Hz, 2 H) 7.3 (s, 1 H) 7.3 (d, J =8.8Hz, 2 H) 7.4 (d, J = 8.1 Hz, 2 H) 8.1 (d, J = 8.1Hz, 2 H) 8.4 (d, J =1.7 Hz, 1 H) 8.7 (s, 1 H)9.2 (s, 1 H)

The compounds of Example Table H have the following chemical names(Example No.):

-   4-{5-[5-(3-Phenyl-prop-1-ynyl)-pyridin-3-yl]-tetrazol-2-ylmethyl}-benzoic    acid (H1);-   4-(5-{5-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-pyridin-3-yl}-tetrazol-2-ylmethyl)-benzoic    acid (H2);-   4-{5-[5-(3-Imidazol-1-yl-prop-1-ynyl)-pyridin-3-yl]-tetrazol-2-ylmethyl}-benzoic    acid (H3); and-   4-(5-{5-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-pyridin-3-yl}-tetrazol-2-ylmethyl)-benzoic    acid (H4).

The compound of Example H2 in Table H above was synthesized according tothe procedure described below.

EXAMPLE H2

4-(5-{5-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-pyridin-3-yl}-tetrazol-2-ylmethyl)-benzoicacid Step (a): 3-Bromo-5-(2H-tetrazol-5-yl)-pyridine

5-Bromo-nicotinonitrile (10.0 g, 55 mmol) was converted to thecorresponding tetrazole (10.8 g, 75%) using the reaction conditionspreviously described in Step (a) of Example 1. ¹HNMR (DMSO-d6) δ 9.17(s, 1H), 8.89 (2, 1H), 8.59 (s, 1H).

Step (b): 4-[5-(5-Bromo-pyridin-3-yl)-tetrazol-2-ylmethyl]-benzoic acidtert-butyl ester

The tetrazole (27.3 g, 104 mmol) from Step (a) was treated with4-bromomethyl-benzoic acid tert-butyl ester (31.0 g, 114 mmol) andcesium carbonate (74.3 g, 228 mmol) in dimethylformamide (400 mL) atroom temperature for 5.5 hours. The solvent was evaporated in vacuo andthe residue passed through a pad of silica gel eluting with CH₂Cl₂:THF19:1, to give a 9:1 mixture of regioisomers (40.07 g, 93%). ¹HNMR(DMSO-d6) δ 9.16 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 7.91 (d, J=8 Hz,2H), 7.51 (d, J=9 Hz, 2H), 6.13 (s, 2H), 1.57 (s, 9H).

Step (c)4-(5-{5-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-pyridin-3-yl}-tetrazol-2-ylmethyl)-benzoicacid tert-butyl ester

The product of Step (b) (300 mg, 0.72 mmol) was mixed with3-(4-(fluorophenyl)-1-propyne (126 mg, 0.94 mmol), diisopropylamine,(0.51 mL, 2.9 mmol) in dimethylformamide (5 mL). The solution wasdegassed. Tetrakis-triphenylphosphine palladium (0) (166 mg, 0.14 mmol),and cuprous iodide (27 mg, 0.14 mmol) were added and the mixturemicrowaved at 120° C. for 1200 seconds. The DMF was removed in vacuo.The crude product was purified by silica gel chromatography, elutingwith dichloromethane:THF 49:1 (124 mg, 37%).

¹HNMR (DMSO-d6) δ 9.12 (s, 1H), 8.78 (s, 1H), 8.36 (s, 1H), 7.89 (d, J=8Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.45 (m, 2H), 7.17 (m, 2H), 6.12 (s, 2H),3.95 (s, 2H), 1.50 (s, 9H).

Step (d)4-(5-{5-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-pyridin-3-yl}-tetrazol-2-ylmethyl)-benzoicacid

The product of Step (c) was treated with trifluoroacetic acid indichloromethane in a manner analogous to that described above in Step(c) of Example 43, then rotary evaporated in vacuo. Trituration of theresulting oil with diethyl ether gave the title product (84 mg, 78%).¹HNMR (DMSO-d6) δ 13.0 (s, 1H), 9.13 (s, 1H), 8.78 (s, 1H), 8.36 (s,1H), 7.93 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.45 (m, 2H), 7.17 (m,2H), 6.13 (s, 2H), 3.95 (s, 2H).

EXAMPLE 11[4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenyl]-aceticacid

M.P. 158-159° C.

EXAMPLE 124-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-cyclohexanecarboxylicacid

MP 172-173° C.

The following compounds of Examples K1 to K3 are compounds of Formula Ithat will be synthesized according to the procedures described above.

EXAMPLE K11-[4-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-phenyl]-cyclopropanecarboxylicacid

EXAMPLE K23-(5-{3-[3-(4-Fluoro-phenyl)-prop-1-ynyl]-phenyl}-tetrazol-2-ylmethyl)-benzoicacid

EXAMPLE K34-{5-[2-(4-Fluoro-benzylcarbamoyl)-6-methyl-pyridin-4-yl]-tetrazol-2-ylmethyl}-benzoicacid

The compounds of Formula I can be evaluated in standard assays for theirability to inhibit the catalytic activity of MMP enzymes. The assaysused to evaluate the MMP biological activity of the invention compoundsare well-known and routinely used by those skilled in the study of MMPinhibitors and their use to treat clinical conditions. For example,compounds of Formula I may be readily identified by assaying a testcompound for inhibition of MMP-13 according to Biological Methods 1 or2, and further assaying the test compound for allosteric inhibition ofMMP-13 according to Biological Methods 3 or 4, as described below.

The compounds of Formula I, as illustrated by the compounds of Examples1 to 37, have been shown to be potent inhibitors of MMP-13 catalyticdomain. Potencies, as measured by IC₅₀'s, with MMP-13 catalytic domainfor the invention compounds typically range from about 0.039 μM to about46 μM. For example, the IC₅₀ of the compound of Example 4 was measuredat 0.039 μM and the IC₅₀ of the compound of Example 2 was measured at0.058 μM.

MMP-13 catalytic domain inhibition data for the compounds of Examples 1to 37 are shown below in Biological Data Table 1 in the columns labelled“MMP-13CD IC₅₀ (μM).”

BIOLOGICAL DATA TABLE 1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) 1 2 3 4 5 6 7 8 9 1011 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 3435 36 37

MMP-13 catalytic domain inhibition for the compounds of Example Table

A are shown below in Biological Table A1 in the columns labelled“MMP-13CD IC₅₀ (μM).”

BIOLOGICAL DATA TABLE A1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) A1 0.44 A2 >3 A3 1.4A4 0.4 A5 1.8 A6 1.0 A7 0.018 A8 1.3 A9 0.0036 A10 N/a N/a means notavailable

MMP-13 catalytic domain inhibition for the compounds of Example Table Bare shown below in Biological Table B1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE B1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) B1 49 B2 0.2 B3 0.014B4 N/a B5 N/a B6 N/a N/a means not available

MMP-13 catalytic domain inhibition for the compounds of Example Table Care shown below in Biological Table C1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE C1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) C1 3.4 C2 0.0011 C3N/a C4 0.0015 N/a means not available

MMP-13 catalytic domain inhibition for the compounds of Example Table Dare shown below in Biological Table D1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE D1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) D1 0.0045 D2 0.013 D30.007 D4 0.15 D5 0.15 D6 2.8 D7 1.3 D8 0.33

MMP-13 catalytic domain inhibition for the compound of Example E1 isshown below in Biological Table E1 in the column labelled “MMP-13CD IC₅₀(μM).”

BIOLOGICAL DATA TABLE E1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) E1 0.058

MMP-13 catalytic domain inhibition for the compounds of Example Table Fare shown below in Biological Table F1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE F1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) F1 0.099 F2 0.28 F30.022 F4 0.21 F5 0.024 F6 0.024 F7 0.11 F8 0.19 F9 16 F10 0.047 F11 11F12 0.0017

MMP-13 catalytic domain inhibition for the compounds of Example Table Gare shown below in Biological Table G1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE G1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) G1 0.69 G2 0.28 G3N/a G4 0.086 G5 0.0068 G6 0.0064 G7 0.029 G8 1.8 N/a means not available

MMP-13 catalytic domain inhibition for the compounds of Example Table Hare shown below in Biological Table H1 in the columns labelled “MMP-13CDIC₅₀ (μM).”

BIOLOGICAL DATA TABLE H1 Ex- Ex- ample MMP-13CD ample MMP-13CD ExampleMMP-13CD No. IC₅₀ (μM) No. IC₅₀ (μM) No. IC₅₀ (μM) H1 0.010¹ H2 0.0083H3 0.16 H4 0.0027 ¹⁾average of two data

The IC₅₀ with MMP-13CD of the compound of Example I1 was 0.0026 μM. TheIC₅₀ with MMP-13CD of the compound of Example I2 was 0.0012 μM.

Invention compounds can be further screened with full-length MMP-2,full-length MMP-7, full-length MMP-9, and MMP-14 catalytic domain todetermine selectivity of the inhibitors with MMP-13 versus the other MMPenzymes also. Selectivities of the invention compounds for MMP-13catalytic domain versus another MMP enzyme (full-length or catalyticdomain), as determined by dividing the IC₅₀ for the inhibitor with acomparator MMP enzyme by the IC₅₀ of the inhibitor with MMP-13 catalyticdomain, are expected to range from 5 to 50,000 fold.

Certain compounds of Formula I have been assayed with MMP-1 full-length,MMP-3 catalytic domain, MMP-7 full-length, MMP-8 full-length, MMP-9full-length, MMP-12 catalytic domain, MMP-14 catalytic domain, andMMP-17 catalytic domain. The IC₅₀'s for the compounds of Example Nos.(“Ex. No.”) C2, C4, F12, and H4 are as shown below in Biological Table 1in the columns labelled “MMP-3CD IC₅₀ (μM),” “MMP-12CD IC₅₀ (μM),”“MMP-14CD IC₅₀ (μM),” and/or “MMP-17CD IC₅₀ (μM).”

BIOLOGICAL TABLE 1 MMP- MMP- MMP- MMP- MMP- MMP- MMP- 3CD MMP- 8FL 9FL12CD 14CD 17CD 1FL IC₅₀ IC₅₀ 7 IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ Ex. No. (μM(μM) (μM) (μM) (μM) (μM) (μM) (μM) C2  >30 100 7.9 >100 >30 N/a¹ 27 >100C4 N/a 4.7 N/a >100 >100 18 >30  30 F12 >100 100 >100 >100 >100 N/a >100N/a H4 >100 4.3 >30 >100 >30 N/a >30 >100

To determine the inhibitory profiles, the compounds of Formula I havebeen evaluated in standard assays for their ability to inhibit thecatalytic activity of various MMP enzymes. The assays used to evaluatethe MMP biological activity of the invention compounds are well-knownand routinely used by those skilled in the study of MMP inhibitors andtheir use to treat clinical conditions.

The assays measure the amount by which a test compound reduces thehydrolysis of a thiopeptolide substrate catalyzed by a matrixmetalloproteinase enzyme. Such assays are described in detail by Ye etal., in Biochemistry, 1992; 31(45): 11231-11235, which is incorporatedherein by reference. One such assay is described below in BiologicalMethod 1.

Some of the particular methods described below use the catalytic domainof the MMP-13 enzyme, namely matrix metalloproteinase-13 catalyticdomain (“MMP-13CD”), rather than the corresponding full-length enzyme,MMP-13. It has been shown previously by Ye Qi-Zhuang, Hupe D., andJohnson L. (Current Medicinal Chemistry, 1996; 3:407-418) that inhibitoractivity against a catalytic domain of an MMP is predictive of theinhibitor activity against the respective full-length MMP enzyme.

Biological Method 1

Thiopeptolide substrates show virtually no decomposition or hydrolysisat or below neutral pH in the absence of a matrix metalloproteinaseenzyme. A typical thiopeptolide substrate commonly utilized for assaysis Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100 μL assay mixture willcontain 50 mM of N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acidbuffer (“HEPES,” pH 7.0), 10 mM CaCl₂, 100 μM thiopeptolide substrate,and 1 mM 5,5′-dithio-bis-(2-nitro-benzoic acid) (DTNB). Thethiopeptolide substrate concentration may be varied, for example from 10to 800 μM to obtain K_(m) and K_(cat) values. The change in absorbanceat 405 nm is monitored on a Thermo Max microplate reader (molecularDevices, Menlo Park, Calif.) at room temperature (22° C.). Thecalculation of the amount of hydrolysis of the thiopeptolide substrateis based on E₄₁₂=13600 M⁻¹ cm⁻¹ for the DTNB-derived product3-carboxy-4-nitrothiophenoxide. Assays are carried out with and withoutmatrix metalloproteinase inhibitor compounds, and the amount ofhydrolysis is compared for a determination of inhibitory activity of thetest compounds.

Test compounds were evaluated at various concentrations in order todetermine their respective IC₅₀ values, the micromolar concentration ofcompound required to cause a 50% inhibition of catalytic activity of therespective enzyme.

It should be appreciated that the assay buffer used with MMP-3CD was 50mM N-morpholinoethane sulfonate (“MES”) at pH 6.0 rather than the HEPESbuffer at pH 7.0 described above.

The test described above for the inhibition of MMP-13 may also beadapted and used to determine the ability of the compounds of Formula Ito inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7,MMP-9, MMP-12 and MMP-14.

Biological Method 2

Some representative compounds of Formula I have been evaluated for theirability to inhibit MMP-13. Inhibitor activity versus other MMPs with thecompounds may be determined using, for example, MMP-1FL, which refers tofull length interstitial collagenase; MMP-2FL, which refers to fulllength Gelatinase A; MMP-3CD, which refers to the catalytic domain ofstromelysin; MMP-7FL, which refers to full length matrilysin; MMP-9FL,which refers to full length Gelatinase B; MMP-13CD, which refers to thecatalytic domain of collagenase 3; and MMP-14CD, which refers to thecatalytic domain of MMP-14. Test compounds can be evaluated at variousconcentrations in order to determine their respective IC₅₀ values, themicromolar concentration of compound required to cause a 50% inhibitionof the hydrolytic activity of the respective enzyme.

The results of the above assays with other MMPs will establish that thecompounds of Formula I are potent inhibitors of MMP enzymes, and areespecially useful due to their selective inhibition of MMP-13. Becauseof this potent and selective inhibitory activity, the compounds areespecially useful to treat diseases mediated by the MMP enzymes.

Allosteric inhibitors of MMP-13 which are compounds of Formula I may bereadily identified by assaying a test compound for inhibition of MMP-13according to the methods described below in Biological Methods 3 and 4.

Biological Method 3

Fluorigenic peptide-1 substrate based assay for identifying compounds ofFormula I as allosteric inhibitors of MMP-13:

Final assay conditions:50 mM HEPES buffer (pH 7.0)

10 mM CaCl₂

10 μM fluorigenic peptide-1 (“FP1”) substrate0 or 15 mM acetohydroxamic acid (AcNHOH)=1 K_(d)2% DMSO (with or without inhibitor test compound)0.5 nM MMP-13CD enzymeStock solutions:1) 10× assay buffer: 500 mM HEPES buffer (pH 7.0) plus 100 mM CaCl₂2) 10 mM FP1 substrate: (Mca)-Pro-Leu-Gly-Leu-(Dnp)-Dpa-Ala-Arg-NH₂(Bachem, M-1895; “A novel coumarin-labeled peptide for sensitivecontinuous assays of the matrix metalloproteinases,” Knight C. G.,Willenbrock F., and Murphy, G., FEBS Lett., 1992; 296:263-266). Isprepared 10 mM stock by dissolving 5 mg FP1 in 0.457 mL DMSO.3) 3 M AcNHOH: Is prepared by adding 4 mL H₂O and 1 mL 10× assay bufferto 2.25 g AcNHOH (Aldrich 15, 903-4). Adjusting pH to 7.0 with NaOH.Diluting volume to 10 mL with H₂O. Final solution will contain 3 MAcNHOH, 50 mM HEPES buffer (pH 7.0), and 10 mM CaCl₂.4) AcNHOH dilution buffer: 50 mM HEPES buffer (pH 7.0) plus 10 mM CaCl₂5) MMP-13CD enzyme: Stock concentration=250 nM.6) Enzyme dilution buffer: 50 mM HEPES buffer (pH 7.0), 10 mM CaCl₂, and0.005% BRIJ 35 detergent (Calbiochem 203728; Protein Grade, 10%)Procedure (for one 96-well microplate):A. Prepared assay mixture:

1100 μL 10× assay buffer

11 μL 10 mM FP1

55 μL 3 M AcNHOH or 55 μL AcNHOH dilution buffer 8500 μL H₂O

B. Diluted MMP-13CD to 5 nM working stock:

22 μL MMP-13CD (250 nM)

1078 μL enzyme dilution buffer

C. Ran kinetic assay:1. Dispense 2 μL inhibitor test sample (in 100% DMSO) into well.2. Add 88 μL assay mixture and mix well, avoiding bubbles.3. Initiate reactions with 10 μL of 5 nM MMP-13CD; mix well, avoidbubbles.4. Immediately measure the kinetics of the reactions at roomtemperature.

-   -   Fluorimeter: F_(max) Fluorescence Microplate Reader & SOFTMAX        PRO Version 1.1 software (Molecular Devices Corporation;        Sunnyvale, Calif. 94089).        -   Protocol menu:

excitation: 320 nm emission: 405 nm run time: 15 min interval: 29 secRFU min: −10 RFU max: 200 V_(max) points: 32/32D. Compared % of control activity and/or IC₅₀ with inhibitor testcompound ±AcNHOH.

Hydrolysis of the fluorigenic peptide-1 substrate,[(Mca)Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂; Bachem, catalog number M-1895],wherein “Mca” is (7-methoxy-coumarin-4-yl)acetyl and “Dpa” is(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl), is used to screen forMMP-13 catalytic domain (CD) inhibitors. (Dpa may also be abbreviated as“Dnp”.) Reactions (100 μL) contain 0.05 M Hepes buffer (pH 7), 0.01 Mcalcium chloride, 0.005% polyoxyethylene (23) lauryl ether (“Brij 35”),0 or 15 mM acetohydroxamic acid, 10 μM FP1, and 0.1 mM to 0.5 nMinhibitor in DMSO (2% final).

After recombinant human MMP-13CD (0.5 nM final) is added to initiate thereaction, the initial velocity of FP1 hydrolysis is determined bymonitoring the increase in fluorescence at 405 nm (upon excitation at320 nm) continuously for up to 30 minutes on a microplate reader at roomtemperature. Alternatively, an endpoint read can also be used todetermine reaction velocity provided the initial fluorescence of thesolution, as recorded before addition of enzyme, is subtracted from thefinal fluorescence of the reaction mixture. The inhibitor is assayed atdifferent concentration values, such as, for example, 100 μM, 10 μM, 1μM, 100 nM, 10 nM, and 1 nM. Then the inhibitor concentration is plottedon the X-axis against the percentage of control activity observed forinhibited experiments versus uninhibited experiments (i.e., (velocitywith inhibitor) divided by (velocity without inhibitor)×100) on theY-axis to determine IC₅₀ values. This determination is done forexperiments done in the presence, and experiments done in the absence,of acetohydroxamic acid. Data are fit to the equation: percent controlactivity=100/[1+(([I]/IC₅₀)slope)], where [α] is the inhibitorconcentration, IC₅₀ is the concentration of inhibitor where the reactionrate is 50% inhibited relative to the control, and slope is the slope ofthe IC₅₀ curve at the curve's inflection point, using nonlinearleast-squares curve-fitting equation regression.

Results may be expressed as an IC₅₀ Ratio (+/−) ratio, which means aratio of the IC₅₀ of the inhibitor with MMP-13 and an inhibitor to thecatalytic zinc of MMP-13, divided by the IC₅₀ of the inhibitor withMMP-13 without the inhibitor to the catalytic zinc of MMP-13. Compoundsof Formula I which are allosteric inhibitors of MMP-13 are expected tohave an IC₅₀ Ratio (+/−) ratio of less than 1, and are expected to besynergistic with the inhibitor to the catalytic zinc of MMP-13 such as,for example, AcNHOH. Compounds of Formula I which are not allostericinhibitors of MMP-13 will be inactive in the assay or will have an IC₅₀Ratio (+/−) of greater than 1, unless otherwise indicated. Results canbe confirmed by kinetics experiments which are well known in thebiochemical art.

Biological Method 4

Fluorigenic peptide-1 based assay for identifying allosteric inhibitorsof matrix metalloproteinase-13 catalytic domain (“MMP-13 CD”):

In a manner similar to Biological Method 3, an assay is run wherein1,10-phenanthouroline is substituted for acetohydroxamic acid toidentify compounds of Formula I.

Animal models may be used to establish that the instant compounds ofFormula I, or a pharmaceutically acceptable salt thereof, would beuseful for preventing, treating, and inhibiting cartilage damage, andthus for treating osteoarthritis, for example. Examples of such animalmodels are described below in Biological Methods 5 and 6.

Biological Method 5 Monosodium Iodoacetate-Induced Osteoarthritis in RatModel of Cartilage Damage (“MIA Rat”):

One end result of the induction of osteoarthritis in this model, asdetermined by histologic analysis, is the development of anosteoarthritic condition within the affected joint, as characterized bythe loss of Toluidine blue staining and formation of osteophytes.Associated with the histologic changes is a concentration-dependentdegradation of joint cartilage, as evidenced by affects on hind-pawweight distribution of the limb containing the affected joint, thepresence of increased amounts of proteoglycan or hydroxyproline in thejoint upon biochemical analysis, or histopathological analysis of theosteoarthritic lesions.

Generally, In the MIA Rat model on Day 0, the hind-paw weightdifferential between the right arthritic joint and the left healthyjoint of male Wistar rats (150 g) are determined with an incapacitancetester, model 2KG (Linton Instrumentation, Norfolk, United Kingdom). Theincapacitance tester has a chamber on top with an outwardly slopingfront wall that supports a rat's front limbs, and two weight sensingpads, one for each hind paw, that facilitates this determination. Thenthe rats are anesthetized with isofluorine, and the right, hind leg kneejoint is injected with 1.0 mg of mono-iodoacetate (“MIA”) thorough theinfrapatellar ligament. Injection of MIA into the joint results in theinhibition of glycolysis and eventual death of surrounding chondrocytes.The rats are further administered either an invention compound orvehicle (in the instant case, water) daily for 14 days or 28 days. Theinvention compound is typically administered at a dose of 30 mg perkilogram of rat per day (30 mg/kg/day), but the invention compound maybe administered at other doses such as, for example, 10 mg/kg/day, 60mg/kg/day, 90-mg/kg/day, or 100 mg/kg/day according to the requirementsof the compound being studied. It is well within the level of ordinaryskill in the pharmaceutical arts to determine a proper dosage of aninvention compound in this model. Administration of the inventioncompound in this model is optionally by oral administration orintravenous administration via an osmotic pump. After 7 and 14 days fora two-week study, or 7, 14, and 28 days for a four-week study, thehind-paw weight distribution is again determined. Typically, the animalsadministered vehicle alone place greater weight on their unaffected lefthind paw than on their right hind paw, while animals administered aninvention compound show a more normal (i.e., more like a healthy animal)weight distribution between their hind paws. This change in weightdistribution was proportional to the degree of joint cartilage damage.Percent inhibition of a change in hind paw joint function is calculatedas the percent change in hind-paw weight distribution for treatedanimals versus control animals. For example, for a two week study,

${{Percent}\mspace{14mu} {inhibition}\mspace{14mu} {of}\mspace{14mu} a\mspace{14mu} {change}\mspace{14mu} {in}\mspace{14mu} {hind}\mspace{14mu} {paw}\mspace{14mu} {weight}\mspace{14mu} {ditribution}} = {\left\{ {1 - \left\lbrack \frac{\left( {\Delta \; W_{G}} \right)}{\left( {\Delta \; W_{C}} \right)} \right\rbrack} \right\} \times 100}$

wherein: ΔW_(C) is the hind-paw weight differential between the healthyleft limb and the arthritic limb of the control animal administeredvehicle alone, as measured on Day 14; and

ΔW_(G) is the hind-paw weight differential between the healthy left limband the arthritic limb of the animal administered an invention compound,as measured on Day 14.

In order to measure biochemical or histopathological end points in theMIA Rat model, some of the animals in the above study may be sacrificed,and the amounts of free proteoglycan in both the osteoarthritic rightknee joint and the contralateral left knee joint may be determined bybiochemical analysis. The amount of free proteoglycan in thecontralateral left knee joint provides a baseline value for the amountof free proteoglycan in a healthy joint. The amount of proteoglycan inthe osteoarthritic right knee joint in animals administered an inventioncompound, and the amount of proteoglycan in the osteoarthritic rightknee joint in animals administered vehicle alone, are independentlycompared to the amount of proteoglycan in the contralateral left kneejoint. The amounts of proteoglycan lost in the osteoarthritic right kneejoints are expressed as percent loss of proteoglycan compared to thecontralateral left knee joint control. The percent inhibition ofproteoglycan loss, may be calculated as {[(proteoglycan loss from joint(%) with vehicle)−(proteoglycan loss from joint with an inventioncompound)]÷(proteoglycan loss from joint (%) with vehicle)}×100.

The MIA Rat data that are expected from the analysis of proteoglycanloss would establish that an invention compound is effective forinhibiting cartilage damage and inflammation and/or alleviating pain inmammalian patients, including human.

The results of these studies with oral dosing may be presented intabular format in the columns labelled “IJFL (%+/−SEM)”, wherein IJFLmeans Inhibition of Joint Function Limitation, “SDCES”, wherein SDCESmeans Significant Decrease In Cartilage Erosion Severity, and “SIJWHLE”,wherein SIJWHLE means Significant Increase in Joints Without Hind LimbErosion.

The proportion of subjects without hind limb erosions may be analyzedvia an Exact Sequential Cochouran-Armitage Trend test (SAS® Institute,1999). The Cochouran-Armitage Trend test is employed when one wishes todetermine whether the proportion of positive or “Yes” respondersincreases or decreases with increasing levels of treatment. For theparticular study, it is expected that the number of animals withoutjoint erosions increased with increasing dose.

The ridit analysis may be used to determine differences in overallerosion severity. This parameter takes into account both the erosiongrade (0=no erosion, I=erosion extending into the superficial or middlelayers, or II=deep layer erosion), and area (small, medium and large,quantified by dividing the area of the largest erosion in each scoreinto thirds) simultaneously. The analysis recognizes that each unit ofseverity is different, but does not assume a mathematical relationshipbetween units.

Another animal model for measuring effects of an invention compound oncartilage damage and inflammation and/or pain is described below inBiological Method 6.

Biological Method 6 Induction of Experimental Osteoarthritis in Rabbit(“EOA in Rabbit”):

Normal rabbits are anaesthetized and anteromedial incisions of the rightknees performed. The anterior cruciate ligaments are visualized andsectioned. The wounds are closed and the animals are housed inindividual cages, exercised, and fed ad libitum. Rabbits are giveneither vehicle (water) or an invention compound dosed three times perday with 30-mg/kg/dose or 10-mg/kg/dose. The invention compound may beadministered at other doses such as, for example, 3 times 20 mg/kg/dayor 3 times 60 mg/kg/day according to the requirements of the inventioncompound being studied. The rabbits are euthanized 8 weeks after surgeryand the proximal end of the tibia and the distal end of the femur areremoved from each animal.

Macroscopic Grading

The cartilage changes on the femoral condyles and tibial plateaus aregraded separately under a dissecting microscope (Stereozoom, Bausch &Lomb, Rochester, N.Y.). The depth of erosion is graded on a scale of 0to 4 as follows: grade 0=normal surface; Grade 1=minimal fibrillation ora slight yellowish discoloration of the surface; Grade 2=erosionextending into superficial or middle layers only; Grade 3=erosionextending into deep layers; Grade 4=erosion extending to subchondralbone. The surface area changes are measured and expressed in mm².Representative specimens may also be used for histologic grading (seebelow).

Histologic Grading

Histologic evaluation is performed on sagittal sections of cartilagefrom the lesional areas of the femoral condyle and tibial plateau.Serial sections (5 um) are prepared and stained with safranin-O. Theseverity of OA lesions is graded on a scale of 0-14 by two independentobservers using the histologic-histochemical scale of Mankin et al. Thisscale evaluates the severity of OA lesions based on the loss ofsafranin-O staining (scale 0-4), cellular changes (scale 0-3), invasionof tidemark by blood vessels (scale 0-1) and structural changes (scale0-6). On this latter scale, 0 indicates normal cartilage structure and 6indicates erosion of the cartilage down to the subchondral bone. Thescoring system is based on the most severe histologic changes in themultiple sections.

Representative specimens of synovial membrane from the medial andlateral knee compartments are dissected from underlying tissues. Thespecimens are fixed, embedded, and sectioned (5 um) as above, andstained with hematoxylin-eosin. For each compartment, two synovialmembrane specimens are examined for scoring purposes and the highestscore from each compartment is retained. The average score is calculatedand considered as a unit for the whole knee. The severity of synovitisis graded on a scale of 0 to 10 by two independent observers, adding thescores of 3 histologic criteria: synovial lining cell hyperplasia (scale0-2); villous hyperplasia (scale 0-3); and degree of cellularinfiltration by mononuclear and polymorphonuclear cells (scale 0-5): 0indicates normal structure.

Statistical Analysis

Mean values and SEM is calculated and statistical analysis was doneusing the Mann-Whitney U-test.

The results of these studies would be expected to show that an inventioncompound would reduce the size of the lesion on the tibial plateaus, andperhaps the damage in the tibia or on the femoral condyles. Inconclusion, these results would show that an invention compound wouldhave significant inhibition effects on the damage to cartilage.

The foregoing studies would establish that an invention compound iseffective for the inhibition of cartilage damage and inflammation and/oralleviating pain, and thus useful for the treatment of osteoarthritis orrheumatoid arthritis in human, and other mammalian disorders. Such atreatment offers a distinct advantage over existing treatments that onlymodify pain or inflammation or and other secondary symptoms. Theeffectiveness of an invention compound in this model would indicate thatthe invention compound will have clinically useful effects in preventingand/or treating cartilage damage, pain and/or inflammation.

Administration according to the invention method of an inventioncompound to a mammal to treat the diseases listed above is preferably,although not necessarily, accomplished by administering the compound, ora salt thereof, in a pharmaceutical dosage form.

The compounds of Formula I, or a pharmaceutically acceptable saltthereof, can be prepared and administered according to the inventionmethod in a wide variety of oral and parenteral pharmaceutical dosageforms. Thus, the compounds of Formula I, or a pharmaceuticallyacceptable salt thereof, can be administered by injection, that is,intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally. Also, the compounds of Formula I,or a pharmaceutically acceptable salt thereof, can be administered byinhalation, for example, intranasally. Additionally, the compounds ofFormula I, or a pharmaceutically acceptable salt thereof, can beadministered transdermally. It will be obvious to those skilled in theart that the following dosage forms may comprise as the active componentan invention compound. The invention compounds generally are present ina concentration of about 5% to about 95% by weight of the formulation.

For preparing pharmaceutical compositions from the compounds of FormulaI, or a pharmaceutically acceptable salt thereof, (i.e., the activecomponent) pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations are preferred. Solid form preparationsinclude powders, tablets, pills, capsules, cachets, suppositories, anddispersible granules. A solid carrier can be one or more substanceswhich may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. Powders suitable forintravenous administration or administration by injection may belyophilized.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from about 5% to about 70%,total, of the active component. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containing anappropriate quantity of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.01 to 1000 mg, preferably 1 to 500 mgaccording to the particular application and the potency of the activecomponents. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as agents to treat the above-listed diseases, thecompounds of Formula I, or a pharmaceutically acceptable salt thereof,are administered at a dose that is effective for treating at least onesymptom of the disease or disorder being treated. The initial dosage ofabout 1 mg/kg to about 100 mg/kg daily of the active component will beeffective. A daily dose range of about 25 mg/kg to about 75 mg/kg of theactive component is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the particular invention compound beingemployed in the invention combination. Determination of the properdosage for a particular situation is within the skill of the art asdescribed above. Typical dosages will be from about 0.1 mg/kg to about500 mg/kg, and ideally about 25 mg/kg to about 250 mg/kg, such that itwill be an amount that is effective to treat the particular disease ordisorder being treated.

A preferred composition for dogs comprises an ingestible liquid peroraldosage form selected from the group consisting of a solution,suspension, emulsion, inverse emulsion, elixir, extract, tincture andconcentrate, optionally to be added to the drinking water of the dogbeing treated. Any of these liquid dosage forms, when formulated inaccordance with methods well known in the art, can either beadministered directly to the dog being treated, or may be added to thedrinking water of the dog being treated. The concentrate liquid form, onthe other hand, is formulated to be added first to a given amount ofwater, from which an aliquot amount may be withdrawn for administrationdirectly to the dog or addition to the drinking water of the dog.

A preferred composition provides delayed-, sustained- and/orcontrolled-release of an invention compound. Such preferred compositionsinclude all such dosage forms which produce ≧40% inhibition of cartilagedegradation, and result in a plasma concentration of the activecomponent of at least 3 fold the active component's ED₄₀ for at least 2hours; preferably for at least 4 hours; preferably for at least 8 hours;more preferably for at least 12 hours; more preferably still for atleast 16 hours; even more preferably still for at least 20 hours; andmost preferably for at least 24 hours. Preferably, there is includedwithin the above-described dosage forms those which produce ≧40%inhibition of cartilage degradation, and result in a plasmaconcentration of the active component of at least 5 fold the activecomponent's ED₄₀ for at least 2 hours, preferably for at least 2 hours,preferably for at least 8 hours, more preferably for at least 12 hours,still more preferably for at least 20 hours and most preferably for atleast 24 hours. More preferably, there is included the above-describeddosage forms which produce ≧50% inhibition of cartilage degradation, andresult in a plasma concentration of the active component of at least 5fold the active component's ED₄₀ for at least 2 hours, preferably for atleast 4 hours, preferably for at least 8 hours, more preferably for atleast 12 hours, still more preferably for at least 20 hours and mostpreferably for at least 24 hours.

The following Formulation Examples 1 to 8 illustrate the inventionpharmaceutical compositions. When the formulations comprise theinvention compound and a pharmaceutically acceptable carrier, diluent,or excipient, they contain a cartilage damage treating effective amountor a therapeutically effective amount such as, for example, ananti-osteoarthritic effective amount of the invention compound. Theexamples are representative only, and are not to be construed aslimiting the invention in any respect.

FORMULATION EXAMPLE 1

Tablet Formulation: Ingredient Amount (mg) An invention compound 25Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste) 10 Magnesiumstearate (1%) 5 Total 100

The invention compound, lactose, and cornstarch (for mix) are blended touniformity. The cornstarch (for paste) is suspended in 200 mL of waterand heated with stirring to form a paste. The paste is used to granulatethe mixed powders. The wet granules are passed thorough a No. 8 handscreen and dried at 80° C. The dry granules are lubricated with the 1%magnesium stearate and pressed into a tablet. Such tablets can beadministered to a human from one to four times a day for inhibitingcartilage damage or treating osteoarthritis.

FORMULATION EXAMPLE 2 Coated Tablets

The tablets of Formulation Example 1 are coated in a customary mannerwith a coating of sucrose, potato starch, talc, tragacanth, andcolorant.

FORMULATION EXAMPLE 3 Injection Vials

The pH of a solution of 500 g of an invention compound and 5 g ofdisodium hydrogen phosphate is adjusted to pH 6.5 in 3 L ofdouble-distilled water using 2 M hydrochloric acid. The solution issterile filtered, and the filtrate is filled into injection vials,lyophilized under sterile conditions, and aseptically sealed. Eachinjection vial contains 25 mg of the invention compound.

FORMULATION EXAMPLE 4 Suppositories

A mixture of 25 g of an invention compound, 100 g of soya lecithin, and1400 g of cocoa butter is fused, poured into molds, and allowed to cool.Each suppository contains 25 mg of the invention compound.

FORMULATION EXAMPLE 5 Solution

A solution is prepared from 1 g of an invention compound, 9.38 g ofNaH₂PO₄.12H₂O, 28.48 g of Na₂HPO₄.12H₂O, and 0.1 g benzalkonium chloridein 940 mL of double-distilled water. The pH of the solution is adjustedto pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0 Lwith double-distilled water, and sterilized by irradiation. A 25 mLvolume of the solution contains 25 mg of the invention compound.

FORMULATION EXAMPLE 6 Ointment

500 mg of an invention compound is mixed with 99.5 g of petroleum jellyunder aseptic conditions. A 5 g portion of the ointment contains 25 mgof the invention compound.

FORMULATION EXAMPLE 7 Capsules

2 kg of an invention compound are filled into hard gelatin capsules in acustomary manner such that each capsule contains 25 mg of the inventioncompound.

FORMULATION EXAMPLE 8 Ampoules

A solution of 2.5 kg of an invention compound is dissolved in 60 L ofdouble-distilled water. The solution is sterile filtered, and thefiltrate is filled into ampoules. The ampoules are lyophilized understerile conditions and aseptically sealed. Each ampoule contains 25 mgof the invention compound.

The following Formulation Examples 9 to 16 illustrate the inventionpharmaceutical compositions containing an invention combination in asingle formulation with a pharmaceutically acceptable carrier, diluent,or excipient. The examples are representative only, and are not to beconstrued as limiting the invention in any respect.

FORMULATION EXAMPLE 9

Tablet Formulation: Ingredient Amount (mg) An invention compound 25 ACOX-2 inhibitor 20 Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste)10 Magnesium stearate (1%) 5 Total 120

The invention compound or COX-2 inhibitor, lactose, and cornstarch (formix) are blended to uniformity. The cornstarch (for paste) is suspendedin 200 mL of water and heated with stirring to form a paste. The pasteis used to granulate the mixed powders. The wet granules are passedthrough a No. 8 hand screen and dried at 80° C. The dry granules arelubricated with the 1% magnesium stearate and pressed into a tablet.Such tablets can be administered to a human from one to four times a dayfor treatment of one of the above-listed diseases.

FORMULATION EXAMPLE 10 Coated Tablets

The tablets of Formulation Example 9 are coated in a customary mannerwith a coating of sucrose, potato starch, talc, tragacanth, andcolorant.

FORMULATION EXAMPLE 11 Injection Vials

The pH of a solution of 250 g of a COX-2 inhibitor, 500 g of aninvention compound, and 5 g of disodium hydrogen phosphate is adjustedto pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid.The solution is sterile filtered, and the filtrate is filled intoinjection vials, lyophilized under sterile conditions, and asepticallysealed. Each injection vial contains 12.5 mg of COX-2 inhibitor and 25mg of the invention compound.

FORMULATION EXAMPLE 12 Suppositories

A mixture of 50 g of a COX-2 inhibitor, 25 g of an invention compound,100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured intomolds, and allowed to cool. Each suppository contains 50 mg of the COX-2inhibitor and 25 mg of the invention compound.

FORMULATION EXAMPLE 13 Solution

A solution is prepared from 0.5 g of a COX-2 inhibitor, 1 g of aninvention compound, 9.38 g of NaH₂PO₄.12H₂O, 28.48 g of Na₂HPO₄.12H₂O,and 0.1 g benzalkonium chloride in 940 mL of double-distilled water. ThepH of the solution is adjusted to pH 6.8 using 2 M hydrochloric acid.The solution is diluted to 1.0 L with double-distilled water, andsterilized by irradiation. A 25 mL volume of the solution contains 12.5mg of the COX-2 inhibitor and 25 mg of the invention compound.

FORMULATION EXAMPLE 14 Ointment

100 mg of a COX-2 inhibitor, 500 mg of an invention compound is mixedwith 99.4 g of petroleum jelly under aseptic conditions. A 5 g portionof the ointment contains 5 mg of the COX-2 inhibitor and 25 mg of theinvention compound.

FORMULATION EXAMPLE 15 Capsules

2 kg of a COX-2 inhibitor and 20 kg of an invention compound are filledinto hard gelatin capsules in a customary manner such that each capsulecontains 25 mg of the COX-2 inhibitor and 250 mg of the inventioncompound.

FORMULATION EXAMPLE 16 Ampoules

A solution of 2.5 kg of a COX-2 inhibitor and 2.5 kg of an inventioncompound is dissolved in 60 L of double-distilled water. The solution issterile filtered, and the filtrate is filled into ampoules. The ampoulesare lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 25 mg each of the COX-2 inhibitor and the inventioncompound.

While it may be desirable to formulate a COX-2 inhibitor and aninvention compound together in one capsule, tablet, ampoule, solution,and the like, for simultaneous administration, it is not necessary forthe purposes of practicing the invention methods. A COX-2 inhibitor andan invention compound alternatively can each be formulated independentlyin any form such as, for example, those of any one Formulation Examples1 to 16, and administered to a patient either simultaneously or atdifferent times.

The following examples illustrate the invention pharmaceuticalcompositions containing discrete formulations of the active componentsof an invention combination and a pharmaceutically acceptable carrier,diluent, or excipient. The examples are representative only, and are notto be construed as limiting the invention in any respect.

FORMULATION EXAMPLE 17

Tablet Formulation of an invention compound: Ingredient Amount (mg) Aninvention compound 25 Lactose 50 Cornstarch (for mix) 10 Cornstarch(paste) 10 Magnesium stearate (1%) 5 Total 100

An invention compound, lactose, and cornstarch (for mix) are blended touniformity. The cornstarch (for paste) is suspended in 200 mL of waterand heated with stirring to form a paste. The paste is used to granulatethe mixed powders. The wet granules are passed through a No. 8 handscreen and dried at 80° C. The dry granules are lubricated with the 1%magnesium stearate and pressed into a tablet.

Injection Vial Formulation of a COX-2 Inhibitor:

The pH of a solution of 500 g of a COX-2 inhibitor and 5 g of disodiumhydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilledwater using 2 M hydrochloric acid. The solution is sterile filtered, andthe filtrate is filled into injection vials, lyophilized under sterileconditions, and aseptically sealed. Each injection vial contains 25 mgof the COX-2 inhibitor.

Such tablets containing the invention compound can be administered to ahuman from one to four times a day for treatment of the above-listeddiseases, and the injection solutions containing the COX-2 inhibitor canbe administered to a human 1 or 2 times per day, wherein theadministration by injection is optionally simultaneous withadministration of the tablets or at different times, for the treatmentof one of the above-listed diseases.

FORMULATION EXAMPLE 18 Coated Tablets Containing an Invention Compound

The tablets of Formulation Example 17 are coated in a customary mannerwith a coating of sucrose, potato starch, talc, tragacanth, andcolorant.

Capsules Containing Valdecoxib or Celecoxib:

2 kg of a COX-2 inhibitor are filled into hard gelatin capsules in acustomary manner such that each capsule contains 25 mg of the COX-2inhibitor.

Such coated tablets containing the invention compound can beadministered to a human from one to four times a day for treatment ofthe above-listed diseases, and the capsules containing the COX-2inhibitor can be administered to a human 1 or 2 times per day, whereinthe administration of the capsules is optionally simultaneous withadministration of the tablets or at different times, for the treatmentof one of the above-listed diseases.

Still further, it should be appreciated that the invention methodscomprising administering an invention combination to a mammal to treatdiseases or disorders listed above may be used to treat differentdiseases simultaneously. For example, administration of a COX-2inhibitor in accordance with the invention combination may be carriedout as described above to treat inflammation, arthritic pain, painassociated with menstrual cramping, and migraines, while an inventioncompound may be administered to treat OA or inhibit cartilage damage.

As shown above, the invention methods comprising administering aninvention compound offer a distinct advantage over existing treatmentsfor diseases such as OA that comprise cartilage damage, wherein theexisting treatments modify pain or secondary symptoms, but do not show adisease modifying effect.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

All references cited above are hereby incorporated by reference herein.

Having described the invention method, various embodiments of theinvention are hereupon claimed.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R²independently are selected from: H; C₁-C₆ alkyl; Substituted C₁-C₆alkyl; C₂-C₆ alkenyl; Substituted C₂-C₆ alkenyl; C₂-C₆ alkynyl;Substituted C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; Substituted C₃-C₆cycloalkyl; C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl); Substituted C₃-C₆cycloalkyl-(C₁-C₆ alkylenyl); 3- to 6-membered heterocycloalkyl;Substituted 3- to 6-membered heterocycloalkyl; 3- to 6-memberedheterocycloalkyl-(C₁-C₆ alkylenyl); Substituted 3- to 6-memberedheterocycloalkyl-(C₁-C₆ alkylenyl); Phenyl-(C₁-C₆ alkylenyl);Substituted phenyl-(C₁-C₆ alkylenyl); Naphthyl-(C₁-C₆ alkylenyl);Substituted naphthyl-(C₁-C₆ alkylenyl); 5-, 6-, 9-, and 10-memberedheteroaryl-(C₁-C₆ alkylenyl); Substituted 5-, 6-, 9-, and 10-memberedheteroaryl-(C₁-C₆ alkylenyl); Phenyl; Substituted phenyl; Naphthyl;Substituted naphthyl; 5-, 6-, 9-, and 10-membered heteroaryl;Substituted 5-, 6-, 9-, and 10-membered heteroaryl; R³O—(C₁-C₆alkylenyl); Substituted R³O—(C₁-C₆ alkylenyl); 5- or 6-memberedheteroaryl; Substituted 5- or 6-membered heteroaryl; 8- to 10-memberedheterobiaryl; Substituted 8- to 10-membered heterobiaryl;Phenyl-O—(C₁-C₈ alkylenyl); Substituted phenyl-O—(C₁-C₈ alkylenyl);Phenyl-S—(C₁-C₈ alkylenyl); Substituted phenyl-S—(C₁-C₈ alkylenyl);Phenyl-S(O)—(C₁-C₈ alkylenyl); Substituted phenyl-S(O)—(C₁-C₈alkylenyl); Phenyl-S(O)₂—(C₁-C₈ alkylenyl); and Substitutedphenyl-S(O)₂—(C₁-C₈ alkylenyl); wherein R¹ and R² are not both selectedfrom: H; C₁-C₆ alkyl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; and C₃-C₆cycloalkyl; Each R³ independently is selected from: H; C₁-C₆ alkyl;Substituted C₁-C₆ alkyl; C₃-C₆ cycloalkyl; Substituted C₃-C₆ cycloalkyl;Phenyl-(C₁-C₆ alkylenyl); Substituted phenyl-(C₁-C₆ alkylenyl);Naphthyl-(C₁-C₆ alkylenyl); Substituted naphthyl-(C₁-C₆ alkylenyl); 5-,6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); Substituted 5-,6-, 9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); Phenyl;Substituted phenyl; Naphthyl; Substituted naphthyl; 5-, 6-, 9-, and10-membered heteroaryl; Substituted 5-, 6-, 9-, and 10-memberedheteroaryl; S, T, U, and W each are C—R⁴; or One of S, T, U, and W is Nand the other three of S, T, U, and W are C—R⁴; or Two of S, T, U, and Ware N and the other two of S, T, U, and W are C—R⁴; or T is C—R⁴ and S,U, and W are each N; or U is C—R⁴ and S, T, and W are each N; or S isC—R⁴ and T, U, and W are each N; Each R⁴ independently is selected from:H; F; CH₃; CF₃; C(O)H; CN; HO; CH₃O; C(F)H₂O; C(H)F₂O; and CF₃O; V is a5-membered heteroarylenyl; and Q is selected from: OCH₂; N(R⁶)CH₂;OC(O); CH(R⁶)C(O); OC(NR⁶); CH(R⁶)C(NR⁶); N(R⁶)C(O); N(R⁶)C(S);N(R⁶)C(NR⁶); N(R⁶)CH₂; SC(O); CH(R⁶)C(S); SC(NR⁶); trans-(H)C═C(H);cis-(H)C═C(H); C≡C; CH₂C≡C; C≡CCH₂; CF₂C≡C; C≡CCF₂;

or V is C(O)O, C(S)O, C(O)N(R⁵), or C(S)N(R⁵); and Q is selected from:OCH₂; N(R⁶)CH₂; CH(R⁶)C(O); OC(NR⁶); CH(R⁶)C(NR⁶); N(R⁶)C(NR⁶);N(R⁶)CH₂; CH(R⁶)C(S); SC(NR⁶); trans-(H)C═C(H); cis-(H)C═C(H); C≡CCH₂;C≡CCF₂;

R⁵ is H or C₁-C₆ alkyl; R⁶ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl; 3- to6-membered heterocycloalkyl; phenyl; benzyl; or 5- or 6-memberedheteroaryl; X is O, S, N(H), or N(C₁-C₆ alkyl); Each V¹ is independentlyC(H) or N; Each “substituted” group contains from 1 to 4 substituents,each independently on a carbon or nitrogen atom, independently selectedfrom: C₁-C₆ alkyl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; C₃-C₆cycloalkylmethyl; Phenyl; Phenylmethyl; 3- to 6-memberedheterocycloalkyl; 3- to 6-membered heterocycloalkylmethyl; cyano; CF₃;(C₁-C₆ alkyl)-OC(O); HOCH₂; (C₁-C₆ alkyl)-OCH₂; H₂NCH₂; (C₁-C₆alkyl)-N(H)CH₂; (C₁-C₆ alkyl)₂-NCH₂; N(H)₂C(O); (C₁-C₆ alkyl)-N(H)C(O);(C₁-C₆ alkyl)₂-NC(O); N(H)₂C(O)N(H); (C₁-C₆ alkyl)-N(H)C(O)N(H);N(H)₂C(O)N(C₁-C₆ alkyl); (C₁-C₆ alkyl)-N(H)C(O)N(C₁-C₆ alkyl); (C₁-C₆alkyl)₂-NC(O)N(H); (C₁-C₆ alkyl)₂-NC(O)N(C₁-C₆ alkyl); N(H)₂C(O)O;(C₁-C₆ alkyl)-N(H)C(O)O; (C₁-C₆ alkyl)₂-NC(O)O; HO; (C₁-C₆ alkyl)-O;CF₃O; CF₂(H)O; CF(H)₂O; H₂N; (C₁-C₆ alkyl)-N(H); (C₁-C₆ alkyl)₂-N; O₂N;(C₁-C₆ alkyl)-S; (C₁-C₆ alkyl)-S(O); (C₁-C₆ alkyl)-S(O)₂; (C₁-C₆alkyl)₂-NS(O)₂; (C₁-C₆ alkyl)-S(O)₂—N(H)—C(O)—(C₁-C₈ alkylenyl)_(m); and(C₁-C₆ alkyl)-C(O)—N(H)—S(O)₂—(C₁-C₈ alkylenyl)_(m); wherein eachsubstituent on a carbon atom may further be independently selected from:Halo; HO₂C; and OCH₂O, wherein each 0 is bonded to adjacent carbon atomsto form a 5-membered ring; wherein 2 substituents may be taken togetherwith a carbon atom to which they are both bonded to form the group C═O;wherein two adjacent, substantially sp² carbon atoms may be takentogether with a diradical substituent to form a cyclic diradicalselected from:

R is H or C₁-C₆ alkyl; m is an integer of 0 or 1; wherein each5-membered heteroarylenyl independently is a 5-membered ring containingcarbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 NH, 1N(C₁-C₆ alkyl), and 4 N, wherein the O and S atoms are not both present,and wherein the heteroarylenyl may optionally be unsubstituted orsubstituted with 1 substituent selected from fluoro, methyl, hydroxy,trifluoromethyl, cyano, and acetyl; wherein each heterocycloalkyl is aring that contains carbon atoms and 1 or 2 heteroatoms independentlyselected from 2 O, 1 S, 1 S(O), 1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆alkyl), and wherein when two O atoms or one O atom and one S atom arepresent, the two O atoms or one O atom and one S atom are not bonded toeach other, and wherein the ring is saturated or optionally contains onecarbon-carbon or carbon-nitrogen double bond; wherein each 5-memberedheteroaryl contains carbon atoms and from 1 to 4 heteroatomsindependently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆ alkyl), and 4 N,and each 6-membered heteroaryl contains carbon atoms and 1 or 2heteroatoms independently selected from N,N(H), and N(C₁-C₆ alkyl), and5- and 6-membered heteroaryl are monocyclic rings; and 9- and10-membered heteroaryl are 6,5-fused and 6,6-fused bicyclic rings,respectively, wherein at least 1 of the 2 fused rings of a bicyclic ringis aromatic, and wherein when the O and S atoms both are present, the Oand S atoms are not bonded to each other; wherein with any (C₁-C₆alkyl)₂-N group, the C₁-C₆ alkyl groups may be optionally taken togetherwith the nitrogen atom to which they are attached to form a 5- or6-membered heterocycloalkyl; and wherein each group and each substituentrecited above is independently selected.
 2. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein V is a5-membered heteroarylenyl; and Q is N(H)C(O).
 3. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein S isN and T, U, and W each are C—R⁴; V is a 5-membered heteroarylenyl; and Qis N(H)C(O).
 4. The compound according to claims 2 or 3, or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is independently selected from: Phenyl-(C₁-C₆ alkylenyl); andSubstituted phenyl-(C₁-C₆ alkylenyl); wherein each group and eachsubstituent is independently selected.
 5. The compound according toclaims 2 or 3, or a pharmaceutically acceptable salt thereof, wherein atleast one of R¹ and R² is independently selected from: 5-, 6-, 9-, and10-membered heteroaryl-(C₁-C₆ alkylenyl); and Substituted 5-, 6-, 9-,and 10-membered heteroaryl-(C₁-C₆ alkylenyl); wherein each heteroarylcontains carbon atoms and from 1 to 4 heteroatoms independently selectedfrom 1 O, 1 S, 1 N(H), 1 N(C₁-C₆ alkyl), and 4 N, and 5- and 6-memberedheteroaryl are monocyclic rings and 9- and 10-membered heteroaryl are6,5-fused and 6,6-fused bicyclic rings, respectively, wherein at least 1of the 2 fused rings of a bicyclic ring is aromatic, and wherein whenthe O and S atoms both are present, the O and S atoms are not bonded toeach other; and wherein each group and each substituent is independentlyselected.
 6. The compound according to claim 4, or a pharmaceuticallyacceptable salt thereof, wherein each C₁-C₆ alkylenyl is CH₂, C(CH₃)₂,C(═O), or CF₂.
 7. The compound according to claim 6, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂.
 8. The compound according to claim 5, or a pharmaceuticallyacceptable salt thereof, wherein each C₁-C₆ alkylenyl is CH₂, C(CH₃)₂,C(═O), or CF₂.
 9. The compound according to claim 8, or apharmaceutically acceptable salt thereof, wherein each C₁-C₆ alkylenylis CH₂.
 10. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is a compound of FormulaIa

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R²independently are selected from: Substituted C₁-C₆ alkyl; SubstitutedC₂-C₆ alkenyl; Substituted C₂-C₆ alkynyl; Substituted C₃-C₆ cycloalkyl;Substituted C₃-C₆ cycloalkyl-(C₁-C₆ alkylenyl); Substituted 3- to6-membered heterocycloalkyl; Substituted 3- to 6-memberedheterocycloalkyl-(C₁-C₆ alkylenyl); Phenyl-(C₁-C₆ alkylenyl);Substituted phenyl-(C₁-C₆ alkylenyl); 5-, 6-, 9-, and 10-memberedheteroaryl-(C₁-C₆ alkylenyl); Substituted 5-, 6-, 9-, and 10-memberedheteroaryl-(C₁-C₆ alkylenyl); Phenyl; Substituted phenyl; 5-, 6-, 9-,and 10-membered heteroaryl; Substituted 5-, 6-, 9-, and 10-memberedheteroaryl; R³O—(C₁-C₆ alkylenyl); Substituted R³O—(C₁-C₆ alkylenyl);Naphthyl; Substituted naphthyl; 5- or 6-membered heteroaryl; Substituted5- or 6-membered heteroaryl; 8- to 10-membered heterobiaryl; Substituted8- to 10-membered heterobiaryl; Phenyl-O—(C₁-C₈ alkylenyl); Substitutedphenyl-O—(C₁-C₈ alkylenyl); Phenyl-S—(C₁-C₈ alkylenyl); Substitutedphenyl-S—(C₁-C₈ alkylenyl); Phenyl-S(O)—(C₁-C₈ alkylenyl); Substitutedphenyl-S(O)—(C₁-C₈ alkylenyl); Phenyl-S(O)₂—(C₁-C₈ alkylenyl); andSubstituted phenyl-S(O)₂—(C₁-C₈ alkylenyl); Each R³ independently isselected from: Substituted C₁-C₆ alkyl; Substituted C₃-C₆ cycloalkyl;Phenyl-(C₁-C₆ alkylenyl); Substituted phenyl-(C₁-C₆ alkylenyl); 5-, 6-,9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); Substituted 5-, 6-,9-, and 10-membered heteroaryl-(C₁-C₆ alkylenyl); 5-, 6-, 9-, and10-membered heteroaryl; Substituted 5-, 6-, 9-, and 10-memberedheteroaryl; S, T, U, and W each are C—R⁴; or One of S, T, U, and W is Nand the other three of S, T, U, and W are C—R⁴; or Two of S, T, U, and Ware N and the other two of S, T, U, and W are C—R⁴; or T is C—R⁴ and S,U, and W are each N; or U is C—R⁴ and S, T, and W are each N; or S isC—R⁴ and T, U, and W are each N; Each R⁴ independently is selected from:H, F, CH₃, CF₃, C(O)H, CN, HO, CH₃O, C(F)H₂O, C(H)F₂O, and CF₃O; V is a5-membered heteroarylenyl; and Q is selected from: OCH₂, N(R⁶)CH₂,OC(O), CH(R⁶)C(O), OC(NR⁶), CH(R⁶)C(NR⁶), N(R⁶)C(O), N(R⁶)C(S),N(R⁶)C(NR⁶), N(R⁶)CH₂, SC(O), CH(R⁶)C(S), SC(NR⁶), trans-(H)C═C(H),cis-(H)C═C(H), C≡C, CH₂C≡C, C≡CCH₂, CF₂C≡C, C≡CCF₂,

or V is C(O)O, C(S)O, C(O)N(R⁵), or C(S)N(R⁵); and Q is selected from:OCH₂, N(R⁶)CH₂, CH(R⁶)C(O), OC(NR⁶), CH(R⁶)C(NR⁶), N(R⁶)C(NR⁶),N(R⁶)CH₂, CH(R⁶)C(S), SC(NR⁶), trans-(H)C═C(H), cis-(H)C═C(H), C≡CCH₂,C≡CCF₂,

R⁵ is H or C₁-C₆ alkyl; R⁶ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl; 3- to6-membered heterocycloalkyl; phenyl; benzyl; or 5- or 6-memberedheteroaryl; X is O, S, N(H), or N(C₁-C₆ alkyl); Each V¹ is independentlyC(H) or N; Each “substituted” group contains from 1 to 4 substituents,each independently on a carbon or nitrogen atom, independently selectedfrom: C₁-C₆ alkyl; C₂-C₆ alkenyl; C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; C₃-C₆cycloalkylmethyl; Phenyl; Phenylmethyl; 3- to 6-memberedheterocycloalkyl; 3- to 6-membered heterocycloalkylmethyl; cyano; CF₃;(C₁-C₆ alkyl)-OC(O); HOCH₂; (C₁-C₆ alkyl)-OCH₂; H₂NCH₂; (C₁-C₆alkyl)-N(H)CH₂; (C₁-C₆ alkyl)₂-NCH₂; N(H)₂C(O); (C₁-C₆ alkyl)-N(H)C(O);(C₁-C₆ alkyl)₂-NC(O); N(H)₂C(O)N(H); (C₁-C₆ alkyl)-N(H)C(O)N(H);N(H)₂C(O)N(C₁-C₆ alkyl); (C₁-C₆ alkyl)-N(H)C(O)N(C₁-C₆ alkyl); (C₁-C₆alkyl)₂-NC(O)N(H); (C₁-C₆ alkyl)₂-NC(O)N(C₁-C₆ alkyl); N(H)₂C(O)O;(C₁-C₆ alkyl)-N(H)C(O)O; (C₁-C₆ alkyl)₂-NC(O)O; HO; (C₁-C₆ alkyl)-O;CF₃O; CF₂(H)O; CF(H)₂O; H₂N; (C₁-C₆ alkyl)-N(H); (C₁-C₆ alkyl)₂-N; O₂N;(C₁-C₆ alkyl)-S; (C₁-C₆ alkyl)-S(O); (C₁-C₆ alkyl)-S(O)₂; (C₁-C₆alkyl)₂-NS(O)₂; (C₁-C₆ alkyl)-S(O)₂—N(H)—C(O)—(C₁-C₈ alkylenyl)_(m);(C₁-C₆ alkyl)-C(O)—N(H)—S(O)₂—(C₁-C₈ alkylenyl)_(m); HO—C(═O)—(C₁-C₃alkylenyl); HO—C(═O)—(C₃-C₆ cycloalkylen-1-yl); Phenyl substituted with1 or two substituents selected from F, Cl, OH, OCH₃, C≡N, COOH, COOCH₃,C(═O)CH₃, and CF₃; 5- or 6-membered heteroaryl; 5- or 6-memberedheteroaryl substituted with 1 substituent selected from F, Cl, OH, OCH₃,C≡N, COOH, COOCH₃, C(═O)CH₃, and CF₃; SO₃H; PO₃H₂; andR⁷R^(7a)-(J)_(m)-N(H)CH₂, wherein m is an integer of 0 or 1; J isN—C(═O); and R⁷ and R^(7a) are independently selected from hydrogen,C₁-C₆ alkyl, (C₁-C₆ alkyl)-C(═O), C₁-C₆ alkyl substituted with 1 or 2OH, C₁-C₃ alkyl-O—(C₁-C₃ alkylenyl), 5- or 6-membered heteroaryl-C(═O),and (C₁-C₆ alkyl)-S(O)₂; or R⁷ and R^(7a) may be taken together with thenitrogen atom to which they are both bonded to form (i) a 3- to6-membered heterocycloalkyl, optionally substituted with a CH₃ or oxo(i.e., ═O), containing the nitrogen atom, 0 or 10 or S atoms, and carbonatoms or (ii) a 5- or 6-membered heteroaryl containing the nitrogenatom, 0 or 1 additional N atom, and carbon atoms; wherein eachsubstituent on a carbon atom may further be independently selected from:Halo; HO₂C; and OCH₂O, wherein each O is bonded to adjacent carbon atomsto form a 5-membered ring; wherein 2 substituents may be taken togetherwith a carbon atom to which they are both bonded to form the group C═O;wherein two adjacent, substantially sp² carbon atoms may be takentogether with a diradical substituent to form a cyclic diradicalselected from:

R is H or C₁-C₆ alkyl; m is an integer of 0 or 1; wherein each5-membered heteroarylenyl independently is a 5-membered ring containingcarbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 NH, 1N(C₁-C₆ alkyl), and 4 N, wherein the O and S atoms are not both present,and wherein the heteroarylenyl may optionally be unsubstituted orsubstituted with 1 substituent selected from fluoro, methyl, hydroxy,trifluoromethyl, cyano, and acetyl; wherein each heterocycloalkyl is aring that contains carbon atoms and 1 or 2 heteroatoms independentlyselected from 2 O, 1 S, 1 S(O), 1 S(O)₂, 1 N, 2 N(H), and 2 N(C₁-C₆alkyl), and wherein when two O atoms or one O atom and one S atom arepresent, the two O atoms or one O atom and one S atom are not bonded toeach other, and wherein the ring is saturated or optionally contains onecarbon-carbon or carbon-nitrogen double bond; wherein each 5-memberedheteroaryl contains carbon atoms and from 1 to 4 heteroatomsindependently selected from 1 O, 1 S, 1 N(H), 1 N(C₁-C₆ alkyl), and 4 N,and each 6-membered heteroaryl contains carbon atoms and 1 or 2heteroatoms independently selected from N,N(H), and N(C₁-C₆ alkyl), and5- and 6-membered heteroaryl are monocyclic rings; and 9- and10-membered heteroaryl are 6,5-fused and 6,6-fused bicyclic rings,respectively, wherein at least 1 of the 2 fused rings of a bicyclic ringis aromatic, and wherein when the O and S atoms both are present, the Oand S atoms are not bonded to each other; wherein with any (C₁-C₆alkyl)₂-N group, the C₁-C₆ alkyl groups may be optionally taken togetherwith the nitrogen atom to which they are attached to form a 5- or6-membered heterocycloalkyl; and wherein each group and each substituentrecited above is independently selected.
 11. The compound according toclaim 10, or a pharmaceutically acceptable salt thereof, wherein S, T,U, and W are each CH or one of S, T, U, and W is N and the other threeof S, T, U, and W are each CH; and Q is C≡C or N(R⁶)C(O).
 12. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, admixed with apharmaceutically acceptable carrier, excipient, or diluent.